Calcium signalling and cell-fate choice in B cells
Nature (2007)
- PubMed: 17853903
Available from www.ncbi.nlm.nih.gov
or
Abstract
It has long been recognized that the cell-cell adhesion receptor, E-cadherin, is an important determinant of tumor progression, serving as a suppressor of invasion and metastasis in many contexts. Yet how the loss of E-cadherin function promotes tumor progression is poorly understood. In this review, we focus on three potential underlying mechanisms: the capacity of E-cadherin to regulate beta-catenin signaling in the canonical Wnt pathway; its potential to inhibit mitogenic signaling through growth factor receptors and the possible links between cadherins and the molecular determinants of epithelial polarity. Each of these potential mechanisms provides insights into the complexity that is likely responsible for the tumor-suppressive action of E-cadherin.
Available from www.ncbi.nlm.nih.gov
Page 1
Calcium signalling and cell-fate choice in B cells
ENDOTHELIAL CELLS IN ALLOGRAFT REJECTION
Rafia S. Al-Lamki, John R. Bradley, and Jordan S. Pober
from the NIHR Cambridge Biomedical Research Centre, Department of Medicine, University of
Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK and the Department of
Immunobiology, Section of Human and Translational Immunology, Yale University School of
Medicine, New Haven, CT, USA 06520-8089
Abstract
In organ transplantation, blood borne cells and macromolecules (e.g. antibodies) of the host immune
system are brought into direct contact with the endothelial cell (EC) lining of graft vessels. In this
location, graft ECs play several roles in allograft rejection, including the initiation of rejection
responses by presentation of alloantigen to circulating T cells; the development of inflammation and
thrombosis; and as targets of injury and agents of repair.
Keywords
antigen presentation; inflammation; leukocyte; lymphocyte; antibody; complement
Introduction
In this review we will summarize the roles that graft endothelial cells (ECs) play in various
stages of the rejection of allografts.
Endothelial Cells as Initiators of Rejection
T cells recognize allografts as non-self either by direct or indirect recognition of alloantigens
(signal 1) (1,2). Direct recognition is initially dominant, involving many more T cell clones,
whereas indirect recognition may become more important at later times. The adaptive immune
response is altered by experience and at least half of all circulating T cells in an adult human
are memory cells (3,4). Naïve and memory T cells have different requirements for activation
(5–7) and patterns of recirculation (8). Memory cells are further subdivided into effector
memory T cells that home to sites of inflammation and central memory T cells that recirculate
through secondary lymphoid organs (8). Memory T cells generally have lesser requirements
for costimulation (signal 2) and are less subject to modulation of their patterns of response by
cytokines (signal 3) (9). They are also harder to immunosuppress, and to regulate (10). There
is a high frequency of alloreactive memory T cells in humans that correlates with the outcome
of clinical transplantation (11). As we will discuss shortly, memory T cells have a special
relationship with ECs that will be described below.
Signals 1 and 2 are normally typically presented to naïve T cells by dendritic cells (DCs),
referred to as “professional” antigen presenting cells (APCs). DCs increase their expression of
MHC peptide complexes and co-stimulators (undergo “maturation”) in response to microbe-
Corresponding Author: Jordan S. Pober, M.D., Ph.D., Yale University School of Medicine, PO Box 208089, New Haven, CT 06520-8089,
email: jordan.pober@yale.edu.
The authors have no conflicts of interest.
NIH Public Access
Author Manuscript
Transplantation. Author manuscript; available in PMC 2009 November 27.
Published in final edited form as:
Transplantation. 2008 November 27; 86(10): 1340–1348. doi:10.1097/TP.0b013e3181891d8b.
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Rafia S. Al-Lamki, John R. Bradley, and Jordan S. Pober
from the NIHR Cambridge Biomedical Research Centre, Department of Medicine, University of
Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK and the Department of
Immunobiology, Section of Human and Translational Immunology, Yale University School of
Medicine, New Haven, CT, USA 06520-8089
Abstract
In organ transplantation, blood borne cells and macromolecules (e.g. antibodies) of the host immune
system are brought into direct contact with the endothelial cell (EC) lining of graft vessels. In this
location, graft ECs play several roles in allograft rejection, including the initiation of rejection
responses by presentation of alloantigen to circulating T cells; the development of inflammation and
thrombosis; and as targets of injury and agents of repair.
Keywords
antigen presentation; inflammation; leukocyte; lymphocyte; antibody; complement
Introduction
In this review we will summarize the roles that graft endothelial cells (ECs) play in various
stages of the rejection of allografts.
Endothelial Cells as Initiators of Rejection
T cells recognize allografts as non-self either by direct or indirect recognition of alloantigens
(signal 1) (1,2). Direct recognition is initially dominant, involving many more T cell clones,
whereas indirect recognition may become more important at later times. The adaptive immune
response is altered by experience and at least half of all circulating T cells in an adult human
are memory cells (3,4). Naïve and memory T cells have different requirements for activation
(5–7) and patterns of recirculation (8). Memory cells are further subdivided into effector
memory T cells that home to sites of inflammation and central memory T cells that recirculate
through secondary lymphoid organs (8). Memory T cells generally have lesser requirements
for costimulation (signal 2) and are less subject to modulation of their patterns of response by
cytokines (signal 3) (9). They are also harder to immunosuppress, and to regulate (10). There
is a high frequency of alloreactive memory T cells in humans that correlates with the outcome
of clinical transplantation (11). As we will discuss shortly, memory T cells have a special
relationship with ECs that will be described below.
Signals 1 and 2 are normally typically presented to naïve T cells by dendritic cells (DCs),
referred to as “professional” antigen presenting cells (APCs). DCs increase their expression of
MHC peptide complexes and co-stimulators (undergo “maturation”) in response to microbe-
Corresponding Author: Jordan S. Pober, M.D., Ph.D., Yale University School of Medicine, PO Box 208089, New Haven, CT 06520-8089,
email: jordan.pober@yale.edu.
The authors have no conflicts of interest.
NIH Public Access
Author Manuscript
Transplantation. Author manuscript; available in PMC 2009 November 27.
Published in final edited form as:
Transplantation. 2008 November 27; 86(10): 1340–1348. doi:10.1097/TP.0b013e3181891d8b.
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Page 2
derived “pathogen-associated molecular patterns” (12) or signals released by injured cells
(“damage-associated molecular patterns” or “alarmins”) (13). The latter may be more relevant
in transplantation because ischemia/reperfusion (I/R) injury during organ transplantation
releases alarmins, maturing DCs within the graft. Alarmins may also directly influence
alloreactive memory T cell responses independently of DCs (14). In a rat kidney transplant
model, graft-derived DCs (“passenger leukocytes") may be required to initiate graft rejection
(15). In mice, allograft rejection by adoptively transferred naïve CD8+ T cells requires their
activation within secondary lymphoid organs by graft-derived DCs (16), but rejection by
adoptively transferred memory CD8+ T cells may occur in the absence of secondary lymphoid
organs (17) and without a need for graft DCs (18). Passenger leukocyte depletion with antibody
failed to prevent rejection of human kidneys although it is difficult to ascertain the completeness
of depletion in this case. Nevertheless, these observations suggest that cells other than DCs
may initiate allograft rejection perhaps through activation of alloreactive memory T cells
(19). Several lines of evidence suggest that human (or mouse) ECs serve as this alternative
initiator of rejection:
(1). In human allografts, vascular ECs basally express both class I and class II MHC molecules
(20,21). (see Table I). In culture, human ECs reduce class I and completely lose expression of
class II molecules; cytokines, including TNF, IFN-α, IFN-β and IFN-γ, can restore class I MHC
molecule expression, but only IFN-γ restores class II expression (22). Human ECs also process
protein antigens to peptides that can be recognized by T cell clones (23). It is unknown if human
ECs process antigens differently from other cell types, although this has been suggested for
viral antigens (24). However, CTL produced by culturing human CD8+ T cells with allogeneic
B lymphoblastoid cells readily recognize allogeneic ECs, implying that common peptides are
generated (25,26). Human ECs differ from mouse ECs in several respects relevant for antigen
presentation (see Table II), and this must be considered when interpreting rodent transplant
experiments.
(2), Cultured human ECs display functional co-stimulators that enhance T cell IL-2 production
(27). While unable to express either CD80 or CD86, the principal costimulators required by
naïve T cells, human ECs express other costimulators that are relevant for the activation of
memory T cells. (see Table I).
(3). Human ECs cultured with resting allogeneic T cells in the absence of professional APCs
stimulate IL-2 production by and proliferation of memory but not naïve T cells (4,7,27). This
capacity distinguishes human ECs from most other cell types in peripheral tissues (28) as well
as from DCs (see Table III). Once activated by ECs, memory T cells can subsequently respond
to other cell types expressing relevant MHC molecules (28). Activation by ECs causes effector
cytokine production from memory CD4+ T cells (29) and maturation of memory CD8+ T cells
into cytolytic T lymphocytes (CTL), some of which are specific for EC targets (30). In mice,
CD8+ but not CD4+ T cells proliferate to cultured allogeneic ECs (31,32). CD4+ T cell
responses to cultured mouse ECs may largely involve activation of regulatory T cell
populations (33). Significantly for transplant rejection, adoptive transfer of resting human
effector memory T cells to an immunodeficient mouse host in the absence of professional APCs
can injure allogeneic human ECs within a human skin graft (29).
Although human graft ECs are capable of directly activating T cells, ECs may play additional
roles in the process of alloantigen recognition. First, EC may promote differentiation of
monocytes into competent APCs (34) and may actually contribute to their differentiation into
DCs (35). Second, host ECs may pick up graft antigens and present them to CD8+ T cells,
displaying the property of "cross-presentation" sometimes proposed as unique to DCs (36).
Al-Lamki et al. Page 2
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(“damage-associated molecular patterns” or “alarmins”) (13). The latter may be more relevant
in transplantation because ischemia/reperfusion (I/R) injury during organ transplantation
releases alarmins, maturing DCs within the graft. Alarmins may also directly influence
alloreactive memory T cell responses independently of DCs (14). In a rat kidney transplant
model, graft-derived DCs (“passenger leukocytes") may be required to initiate graft rejection
(15). In mice, allograft rejection by adoptively transferred naïve CD8+ T cells requires their
activation within secondary lymphoid organs by graft-derived DCs (16), but rejection by
adoptively transferred memory CD8+ T cells may occur in the absence of secondary lymphoid
organs (17) and without a need for graft DCs (18). Passenger leukocyte depletion with antibody
failed to prevent rejection of human kidneys although it is difficult to ascertain the completeness
of depletion in this case. Nevertheless, these observations suggest that cells other than DCs
may initiate allograft rejection perhaps through activation of alloreactive memory T cells
(19). Several lines of evidence suggest that human (or mouse) ECs serve as this alternative
initiator of rejection:
(1). In human allografts, vascular ECs basally express both class I and class II MHC molecules
(20,21). (see Table I). In culture, human ECs reduce class I and completely lose expression of
class II molecules; cytokines, including TNF, IFN-α, IFN-β and IFN-γ, can restore class I MHC
molecule expression, but only IFN-γ restores class II expression (22). Human ECs also process
protein antigens to peptides that can be recognized by T cell clones (23). It is unknown if human
ECs process antigens differently from other cell types, although this has been suggested for
viral antigens (24). However, CTL produced by culturing human CD8+ T cells with allogeneic
B lymphoblastoid cells readily recognize allogeneic ECs, implying that common peptides are
generated (25,26). Human ECs differ from mouse ECs in several respects relevant for antigen
presentation (see Table II), and this must be considered when interpreting rodent transplant
experiments.
(2), Cultured human ECs display functional co-stimulators that enhance T cell IL-2 production
(27). While unable to express either CD80 or CD86, the principal costimulators required by
naïve T cells, human ECs express other costimulators that are relevant for the activation of
memory T cells. (see Table I).
(3). Human ECs cultured with resting allogeneic T cells in the absence of professional APCs
stimulate IL-2 production by and proliferation of memory but not naïve T cells (4,7,27). This
capacity distinguishes human ECs from most other cell types in peripheral tissues (28) as well
as from DCs (see Table III). Once activated by ECs, memory T cells can subsequently respond
to other cell types expressing relevant MHC molecules (28). Activation by ECs causes effector
cytokine production from memory CD4+ T cells (29) and maturation of memory CD8+ T cells
into cytolytic T lymphocytes (CTL), some of which are specific for EC targets (30). In mice,
CD8+ but not CD4+ T cells proliferate to cultured allogeneic ECs (31,32). CD4+ T cell
responses to cultured mouse ECs may largely involve activation of regulatory T cell
populations (33). Significantly for transplant rejection, adoptive transfer of resting human
effector memory T cells to an immunodeficient mouse host in the absence of professional APCs
can injure allogeneic human ECs within a human skin graft (29).
Although human graft ECs are capable of directly activating T cells, ECs may play additional
roles in the process of alloantigen recognition. First, EC may promote differentiation of
monocytes into competent APCs (34) and may actually contribute to their differentiation into
DCs (35). Second, host ECs may pick up graft antigens and present them to CD8+ T cells,
displaying the property of "cross-presentation" sometimes proposed as unique to DCs (36).
Al-Lamki et al. Page 2
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Page 3
The ability of ECs to stimulate alloreactive effector memory CD4+ T cells to secrete IFN-γ
may have a special role in chronic allograft vasculopathy. This lesion, which is the major cause
of late cardiac graft loss (and probably late renal graft loss as well) may depend on local IFN-
γ production within the vessel wall (37). Histological analysis of these lesions in allograft
coronary arteries suggests the persistence of graft ECs (38) in direct contact with subjacent
host T cells (39). ECs may further contribute to chronic allograft vasculopathy by acting as a
source of signals that induce bystander T cells to express inducible nitric oxide synthase, a
signal that may help sustain alloresponses (40).
ECs as Participants in Rejection
Allograft rejection involves recruitment and activation of circulating leukocytes in response
to co-ordinated changes in microvascular ECs (reviewed in (41)). Pro-inflammatory alterations
in ECs is termed “activation” (41). Type I activation is mediated in response to ligands such
as histamine or thrombin, and occurs independently of protein synthesis within minutes.
Examples are NO or prostaglandin production or P-selectin translocation from storage
organelles (Weibel-Palade bodies) to the cell surface. Type II activation is induced by cytokines
such as TNF or IL-1, and involves transcription of new genes such as the adhesion molecules
E-selectin, ICAM-1 and VCAM-1. Both responses may contribute to vascular leakiness, a
cardinal feature of inflammation, although type II activation causes more sustained junctional
changes and vascular leak. Key changes in activated venular ECs that contribute to leukocyte
recruitment are expression of adhesion molecules that bind leukocytes and display of
chemokines that activate the captured leukocytes. (see Table IV). The relevant EC adhesion
molecules and activating chemokines responsible for leukocyte recruitment vary with
particular leukocyte populations. Monocyte recruitment into rejecting human renal allografts
may depend particularly upon EC selectins and the chemokines MCP-1 (CCL2) and RANTES
(CCL5) that bind to chemokine receptors CCR1, CCR2 and CCR5 (42). Inflammatory T cells,
especially those that have differentiated into effector memory T cells, more readily interact
with VCAM-1 and with chemokines that bind to the receptor designated CXCR3, namely Mig
(CXCL9) IP-10 (CXCL10) and ITAC (CXCL11) (43) and ENA-78 (CXCL5) (44). Both
RANTES and IP-10 expression correlate with T cell infiltration into rejecting renal allografts
(45,46). In vitro, T cells, but not monocytes, require shear stress to initiate transmigration
(43,47). ECs may further contribute to leukocyte recruitment by forming a cup-like extension
of the plasma membrane at sites of transmigration (48). This structure may form away from
intercellular junctions allowing leukocytes to pass through the EC body.
EC functions related to antigen presentation and leukocyte recruitment may be linked. Antigen-
activated T cells are a major source of cytokines that mediate type II EC activation, including
TNF and lymphotoxin (LT, also called LTα or TNFβ). Antigen-activated T cells may also
activate ECs through a contact-dependent pathway utilizing CD154 (49). EC antigen
presentation to effector memory T cells may trigger T cell diapedesis involving the cytokine-
inducible transmembrane chemokine fractalkine (CX3CL1) and its receptor (CX3CR1) on
effector memory T cells (50).
ECs may also contribute to graft vessel thrombosis that can exacerbate graft injury (51). Resting
ECs keep blood fluid (41) by preventing platelet activation and displaying tissue factor pathway
inhibitors and inhibitors of thrombin, such as heparan sulfates (51). If thrombin is generated,
resting ECs capture the active enzyme on thrombomodulin and use it to activate protein C,
which degrades clotting factors. ECs also produce plasminogen activators that lead to lysis of
fibrin thrombi. Type II activated EC synthesize express pro-coagulant molecules. At the same
time EC injury (see below) abrogates EC anti-coagulant properties. Although thrombosis may
be observed in acute cell-mediated rejection (ACR), it is more characteristically associated
with antibody-mediated rejection (AMR) (52).
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may have a special role in chronic allograft vasculopathy. This lesion, which is the major cause
of late cardiac graft loss (and probably late renal graft loss as well) may depend on local IFN-
γ production within the vessel wall (37). Histological analysis of these lesions in allograft
coronary arteries suggests the persistence of graft ECs (38) in direct contact with subjacent
host T cells (39). ECs may further contribute to chronic allograft vasculopathy by acting as a
source of signals that induce bystander T cells to express inducible nitric oxide synthase, a
signal that may help sustain alloresponses (40).
ECs as Participants in Rejection
Allograft rejection involves recruitment and activation of circulating leukocytes in response
to co-ordinated changes in microvascular ECs (reviewed in (41)). Pro-inflammatory alterations
in ECs is termed “activation” (41). Type I activation is mediated in response to ligands such
as histamine or thrombin, and occurs independently of protein synthesis within minutes.
Examples are NO or prostaglandin production or P-selectin translocation from storage
organelles (Weibel-Palade bodies) to the cell surface. Type II activation is induced by cytokines
such as TNF or IL-1, and involves transcription of new genes such as the adhesion molecules
E-selectin, ICAM-1 and VCAM-1. Both responses may contribute to vascular leakiness, a
cardinal feature of inflammation, although type II activation causes more sustained junctional
changes and vascular leak. Key changes in activated venular ECs that contribute to leukocyte
recruitment are expression of adhesion molecules that bind leukocytes and display of
chemokines that activate the captured leukocytes. (see Table IV). The relevant EC adhesion
molecules and activating chemokines responsible for leukocyte recruitment vary with
particular leukocyte populations. Monocyte recruitment into rejecting human renal allografts
may depend particularly upon EC selectins and the chemokines MCP-1 (CCL2) and RANTES
(CCL5) that bind to chemokine receptors CCR1, CCR2 and CCR5 (42). Inflammatory T cells,
especially those that have differentiated into effector memory T cells, more readily interact
with VCAM-1 and with chemokines that bind to the receptor designated CXCR3, namely Mig
(CXCL9) IP-10 (CXCL10) and ITAC (CXCL11) (43) and ENA-78 (CXCL5) (44). Both
RANTES and IP-10 expression correlate with T cell infiltration into rejecting renal allografts
(45,46). In vitro, T cells, but not monocytes, require shear stress to initiate transmigration
(43,47). ECs may further contribute to leukocyte recruitment by forming a cup-like extension
of the plasma membrane at sites of transmigration (48). This structure may form away from
intercellular junctions allowing leukocytes to pass through the EC body.
EC functions related to antigen presentation and leukocyte recruitment may be linked. Antigen-
activated T cells are a major source of cytokines that mediate type II EC activation, including
TNF and lymphotoxin (LT, also called LTα or TNFβ). Antigen-activated T cells may also
activate ECs through a contact-dependent pathway utilizing CD154 (49). EC antigen
presentation to effector memory T cells may trigger T cell diapedesis involving the cytokine-
inducible transmembrane chemokine fractalkine (CX3CL1) and its receptor (CX3CR1) on
effector memory T cells (50).
ECs may also contribute to graft vessel thrombosis that can exacerbate graft injury (51). Resting
ECs keep blood fluid (41) by preventing platelet activation and displaying tissue factor pathway
inhibitors and inhibitors of thrombin, such as heparan sulfates (51). If thrombin is generated,
resting ECs capture the active enzyme on thrombomodulin and use it to activate protein C,
which degrades clotting factors. ECs also produce plasminogen activators that lead to lysis of
fibrin thrombi. Type II activated EC synthesize express pro-coagulant molecules. At the same
time EC injury (see below) abrogates EC anti-coagulant properties. Although thrombosis may
be observed in acute cell-mediated rejection (ACR), it is more characteristically associated
with antibody-mediated rejection (AMR) (52).
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ECs as Targets of Rejection
Allograft ECs are a primary target of rejection. Cells and molecules that contribute to rejection
through their actions on ECs include:
(1). Cytolytic T Lymphocytes (CTL)
Direct recognition of a specific complex of peptide and non-self class I MHC molecules on
graft EC by host CTL is a major mechanism of ACR in immunosuppressed patients, leading
to graft cell apoptosis (53,54). The presence of CTL and CTL-specific mRNAs in biopsies
correlates with ACR (55). CTL generated from CD8+ memory T cells by co-culture with
allogeneic ECs may only kill ECs (30), and EC-selective CTL have been recovered from
rejecting grafts (56). EC lysis by CTL involves either T cell ligands that engage death receptors
(DRs, see below) on ECs or granule exocytosis of effector molecules (57). Both pathways
require cell-cell contact and are initiated by recognition of non-self class I MHC/peptide
complexes. Granule exocytosis deposits perforin and granzyme B from the CTL on the target
cell surface. Perforin facilitates entry of granzyme B, a serine protease that cleaves and activates
pro-capsase 3, an effector of apoptosis. The activation and activity of caspase 3 may be held
in check by X-linked Inhibitor of Apoptosis Protein (x-IAP). Granzyme B also cleaves and
activates pro-caspase 8, which may cleave and activate pro-caspase 3, and may also cleave and
activate the cytosolic protein Bid. Activated Bid interacts with Bax, a pro-apoptotic member
of the Bcl-2 family, inducing Bax to dimerize in the outer mitochondrial membrane and initiate
release of proteins that promote cell death, including cytochrome c, Apoptosis Inducing Factor
(AIF) and Second Mediator of Apoptotic Cell death (SMAC, also known as Diablo). This Bax-
mediated release reaction is antagonized by anti-apoptotic members of the Bcl-2 family,
including Bcl-2 itself. SMAC/Diablo prevents x-IAP from inhibiting caspase 3 activation.
Cytochrome c interacts with Apoptotic Protein Activating Factor-1 (APAF-1) to activate
procaspase 9, an alternative activator of caspase-3. AIF leads to cell death independent of
caspases. CTL-mediated killing of cultured human ECs depends granule exocytosis and can
be inhibited by overexpression of Bcl-2, implying a role for mitochondrial release of SMAC-
Diablo in this cell type (58).
(2). Natural Killer (NK) cells
NK cells infiltrate grafts shortly after transplantation (59) and typically recognize targets by a
combination of activating and inhibitory receptors (60). Activating receptors recognize ligands
such as the Fc portions of antibodies, enabling antibody-dependent cell-mediated cytotoxicity
(ADCC), or molecules such as MHC class I-related antigen-A-1 (MICA-1). ADCC may be a
major component of acute AMR in which ECs are primary targets of alloantibody (see below).
NK cell inhibitory receptors often recognize specific allelic forms of class I MHC molecules
complexed to self-peptides but cannot recognize allogeneic cells that lack these molecules
(“absent self”). In the absence of inhibitory signals, host NK cells will recognize and kill
allogeneic ECs (61). NK cell-mediated EC killing has been invoked as a primary pathway of
hyperacute and accelerated acute rejection of xenografts (62) and has been proposed to play a
role in chronic allograft vasculopathy (63). A role for NK cells in ACR of allografts is less
clear. NK cell killing utilizes the same mechanisms as CTL, namely engaging DR ligands and
granule exocytosis of effector molecules.
(3). Macrophages
Monocytes infiltrate kidneys undergoing ACR or AMR and differentiate into macrophages,
which contribute to rejection (64). Macrophages have been associated with capillary regression
during development by inducing EC apoptosis (65); similar events may occur during rejection.
EC injury by macrophages may involve multiple effector mechanisms including elaboration
of TNF, TRAIL, reactive oxygen species (ROS) and NO. The expression of these effectors can
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Allograft ECs are a primary target of rejection. Cells and molecules that contribute to rejection
through their actions on ECs include:
(1). Cytolytic T Lymphocytes (CTL)
Direct recognition of a specific complex of peptide and non-self class I MHC molecules on
graft EC by host CTL is a major mechanism of ACR in immunosuppressed patients, leading
to graft cell apoptosis (53,54). The presence of CTL and CTL-specific mRNAs in biopsies
correlates with ACR (55). CTL generated from CD8+ memory T cells by co-culture with
allogeneic ECs may only kill ECs (30), and EC-selective CTL have been recovered from
rejecting grafts (56). EC lysis by CTL involves either T cell ligands that engage death receptors
(DRs, see below) on ECs or granule exocytosis of effector molecules (57). Both pathways
require cell-cell contact and are initiated by recognition of non-self class I MHC/peptide
complexes. Granule exocytosis deposits perforin and granzyme B from the CTL on the target
cell surface. Perforin facilitates entry of granzyme B, a serine protease that cleaves and activates
pro-capsase 3, an effector of apoptosis. The activation and activity of caspase 3 may be held
in check by X-linked Inhibitor of Apoptosis Protein (x-IAP). Granzyme B also cleaves and
activates pro-caspase 8, which may cleave and activate pro-caspase 3, and may also cleave and
activate the cytosolic protein Bid. Activated Bid interacts with Bax, a pro-apoptotic member
of the Bcl-2 family, inducing Bax to dimerize in the outer mitochondrial membrane and initiate
release of proteins that promote cell death, including cytochrome c, Apoptosis Inducing Factor
(AIF) and Second Mediator of Apoptotic Cell death (SMAC, also known as Diablo). This Bax-
mediated release reaction is antagonized by anti-apoptotic members of the Bcl-2 family,
including Bcl-2 itself. SMAC/Diablo prevents x-IAP from inhibiting caspase 3 activation.
Cytochrome c interacts with Apoptotic Protein Activating Factor-1 (APAF-1) to activate
procaspase 9, an alternative activator of caspase-3. AIF leads to cell death independent of
caspases. CTL-mediated killing of cultured human ECs depends granule exocytosis and can
be inhibited by overexpression of Bcl-2, implying a role for mitochondrial release of SMAC-
Diablo in this cell type (58).
(2). Natural Killer (NK) cells
NK cells infiltrate grafts shortly after transplantation (59) and typically recognize targets by a
combination of activating and inhibitory receptors (60). Activating receptors recognize ligands
such as the Fc portions of antibodies, enabling antibody-dependent cell-mediated cytotoxicity
(ADCC), or molecules such as MHC class I-related antigen-A-1 (MICA-1). ADCC may be a
major component of acute AMR in which ECs are primary targets of alloantibody (see below).
NK cell inhibitory receptors often recognize specific allelic forms of class I MHC molecules
complexed to self-peptides but cannot recognize allogeneic cells that lack these molecules
(“absent self”). In the absence of inhibitory signals, host NK cells will recognize and kill
allogeneic ECs (61). NK cell-mediated EC killing has been invoked as a primary pathway of
hyperacute and accelerated acute rejection of xenografts (62) and has been proposed to play a
role in chronic allograft vasculopathy (63). A role for NK cells in ACR of allografts is less
clear. NK cell killing utilizes the same mechanisms as CTL, namely engaging DR ligands and
granule exocytosis of effector molecules.
(3). Macrophages
Monocytes infiltrate kidneys undergoing ACR or AMR and differentiate into macrophages,
which contribute to rejection (64). Macrophages have been associated with capillary regression
during development by inducing EC apoptosis (65); similar events may occur during rejection.
EC injury by macrophages may involve multiple effector mechanisms including elaboration
of TNF, TRAIL, reactive oxygen species (ROS) and NO. The expression of these effectors can
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be enhanced by IFN-γ-mediated macrophage activation (66). Macrophages may undergo an
alternative pathway of activation, differentiating into “M2 cells” that are distinct from IFN-γ-
activated “M1 cells”. M2 cells are associated with tissue repair but may also promote fibrosis
in late graft loss (66).
(4). Neutrophils
Neutrophils are usually the first cell type recruited into inflammatory responses and their
paucity in the infiltrates associated with ACR is striking. It is possible that they are transiently
recruited at the very earliest stages of the acute rejection process and have disappeared by the
time biopsies are taken. This idea is supported by the observation that E-selectin expression
by ECs in human cardiac biopsies, which is important for neutrophil recruitment, is transient
and predictive of imminent rejection and absent during rejection responses (67,68). Neutrophils
are more common in AMR or in non-immune injury to ECs (see below) and reduction of
neutrophil infiltrates in the peri-operative period reduces subsequent T cell-mediated rejection
of mouse cardiac allografts (69). Injury of EC depends on neutrophil activation and neutrophils
may be activated by cytokines, chemokines, antibodies and complement products. Activated
neutrophils may release both ROS and degradative enzymes that contribute to killing of
microbes; these effector molecules are also capable of injuring or killing ECs.
(5). Death receptor ligands
DRs are members of the TNF receptor superfamily that contain an intracellular protein-protein
interaction domain called a death domain (DD) (70,71). DRs expressed on ECs include TNFR1
(also known as DR1), Fas (also known as DR2), DR3, TRAIL-R1 (also known as DR4) and
TRAIL-R2 (also known as DR5). TNFR1 binds both TNF and lymphotoxin, made primarily
by activated leukocytes, whereas DR3 binds TNF-like molecule 1A (TL1A), which is made
by ECs and activated leukocytes (72). TNF, LT and TL1A are found in rejecting allografts
(73). Fas binds FasL, whereas the two TRAIL receptors bind TRAIL. These membrane-
associated ligands are expressed on activated effector cells, such as CD4+ effector T cells,
CD8+ CTL, NK cells or macrophages, and can mediate cell-cell contact-dependent killing. In
most cells, DR-initiated killing involves activation of DR-linked pro-caspase 8. This has been
shown to occur in cultured human ECs and is enhanced by IFN-γ treatment which increases
pro-caspase 8 expression (74). IFN-γ also allows TNFR1 to initiate a caspase-independent
death pathway in ECs that is initiated by the lysosomal enzyme cathepsin B and involves Bid-
independent release of AIF from mitochondria (75).
In the kidney TNFR1 is expressed basally on glomerular and vascular ECs and is
downregulated during ACR or ischemia/reperfusion (I/R) injury (76). Transcripts and protein
for DR3 are induced in vascular ECs (and renal tubular epithelial cells) in human kidney
allografts undergoing either ACR or I/R injury (77). TNFR1 signaling appears responsible for
TNFR1 downregulation (78). Signaling through TNFR2, which is not a DR and which is
minimally expressed in normal kidney, upregulates TNFR2 expression on ECs and on tubular
epthelial cells (78). Whereas TNFR1 signals lead to inflammation and apoptosis, TNFR2
signals promote proliferation and repair (78). Signals that induce DR3 are unknown and signals
through DR3 are initiated by binding of TL1A (72). TL1A protein is synthesized by ECs in
normal human kidney and synthesis is increased in rejection (73). In organ cultures of normal
human kidney and wild-type mice, TL1A activates NF-κB, induces caspase-3 and apoptosis,
and upregulates TNFR2 in TEC. In DR3 null mice, TL1A does not induce NF-κB or caspase-3
activation but still upregulates TNFR2, suggesting there is a second receptor for TL1A (73).
(6). Antibodies and complement
AMR is characterized by monocyte margination against EC and by capillaries containing
thrombi and fibrinoid arterial necrosis (52). Antibody and complement components are present
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alternative pathway of activation, differentiating into “M2 cells” that are distinct from IFN-γ-
activated “M1 cells”. M2 cells are associated with tissue repair but may also promote fibrosis
in late graft loss (66).
(4). Neutrophils
Neutrophils are usually the first cell type recruited into inflammatory responses and their
paucity in the infiltrates associated with ACR is striking. It is possible that they are transiently
recruited at the very earliest stages of the acute rejection process and have disappeared by the
time biopsies are taken. This idea is supported by the observation that E-selectin expression
by ECs in human cardiac biopsies, which is important for neutrophil recruitment, is transient
and predictive of imminent rejection and absent during rejection responses (67,68). Neutrophils
are more common in AMR or in non-immune injury to ECs (see below) and reduction of
neutrophil infiltrates in the peri-operative period reduces subsequent T cell-mediated rejection
of mouse cardiac allografts (69). Injury of EC depends on neutrophil activation and neutrophils
may be activated by cytokines, chemokines, antibodies and complement products. Activated
neutrophils may release both ROS and degradative enzymes that contribute to killing of
microbes; these effector molecules are also capable of injuring or killing ECs.
(5). Death receptor ligands
DRs are members of the TNF receptor superfamily that contain an intracellular protein-protein
interaction domain called a death domain (DD) (70,71). DRs expressed on ECs include TNFR1
(also known as DR1), Fas (also known as DR2), DR3, TRAIL-R1 (also known as DR4) and
TRAIL-R2 (also known as DR5). TNFR1 binds both TNF and lymphotoxin, made primarily
by activated leukocytes, whereas DR3 binds TNF-like molecule 1A (TL1A), which is made
by ECs and activated leukocytes (72). TNF, LT and TL1A are found in rejecting allografts
(73). Fas binds FasL, whereas the two TRAIL receptors bind TRAIL. These membrane-
associated ligands are expressed on activated effector cells, such as CD4+ effector T cells,
CD8+ CTL, NK cells or macrophages, and can mediate cell-cell contact-dependent killing. In
most cells, DR-initiated killing involves activation of DR-linked pro-caspase 8. This has been
shown to occur in cultured human ECs and is enhanced by IFN-γ treatment which increases
pro-caspase 8 expression (74). IFN-γ also allows TNFR1 to initiate a caspase-independent
death pathway in ECs that is initiated by the lysosomal enzyme cathepsin B and involves Bid-
independent release of AIF from mitochondria (75).
In the kidney TNFR1 is expressed basally on glomerular and vascular ECs and is
downregulated during ACR or ischemia/reperfusion (I/R) injury (76). Transcripts and protein
for DR3 are induced in vascular ECs (and renal tubular epithelial cells) in human kidney
allografts undergoing either ACR or I/R injury (77). TNFR1 signaling appears responsible for
TNFR1 downregulation (78). Signaling through TNFR2, which is not a DR and which is
minimally expressed in normal kidney, upregulates TNFR2 expression on ECs and on tubular
epthelial cells (78). Whereas TNFR1 signals lead to inflammation and apoptosis, TNFR2
signals promote proliferation and repair (78). Signals that induce DR3 are unknown and signals
through DR3 are initiated by binding of TL1A (72). TL1A protein is synthesized by ECs in
normal human kidney and synthesis is increased in rejection (73). In organ cultures of normal
human kidney and wild-type mice, TL1A activates NF-κB, induces caspase-3 and apoptosis,
and upregulates TNFR2 in TEC. In DR3 null mice, TL1A does not induce NF-κB or caspase-3
activation but still upregulates TNFR2, suggesting there is a second receptor for TL1A (73).
(6). Antibodies and complement
AMR is characterized by monocyte margination against EC and by capillaries containing
thrombi and fibrinoid arterial necrosis (52). Antibody and complement components are present
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on the EC surface, and C4d deposition is now taken as evidence of AMR (79) but the lectin
pathway of complement activation, which can be triggered by ischemia, could also lead to
endothelial C4d deposits. The diagnosis of AMR is supported by detection of circulating
antibodies that recognize graft ECs (54). Such antibodies most often react with HLA-A, B, C
and DR antigens, but circulating anti-EC antibodies that react with non-HLA alloantigens have
been detected in patients (80). Some non-HLA alloantigens are shared by ECs and monocytes
but not lymphocytes (E-M antigens), and some are only found on ECs (E antigens). MICA on
renal endothelium is also a potential target for AMR. AMR to ECs may involve complement
and complement-induced inflammation and/or NK cells, which recognize bound antibodies
via Fc receptor and mediate ADCC (81).
In addition to killing ECs via complement activation or targeting NK cells for ADCC,
alloantibodies may activate ECs. Anti-MHC antibodies activate ECs to degranulate Weibel-
Palade bodies, leading to release of IL-8 and display of P-selectin. In culture and in humans
skin grafts placed on immunodeficient mice, F(ab)’ fragments of an HLA-A,B,C antibody can
exert such effects despite their inability to engage Fc receptors or active complement (82).
Anti-class I antibodies may also be mitogenic for ECs, although the role of this response to
allograft rejection is unclear. Activation of the complement system may also affect ECs
independent of antibody, causing perturbation in EC barrier function retraction of EC plasma
membrane from the underlying substrate, release of preformed von Willebrand factor and P-
selectin from Weibel-Palade bodies to the cell surface, and production of cytokines including
IL-α, IL-8 and MCP-1 (83). The combination of C5a and antibody binding can cause ECs to
shed anti-coagulant heparan sulfates (84). ECs express a variety of complement receptors and
complement regulatory proteins that may modulate these responses (85,86). There is little
evidence to date that any of these are actively regulated in allograft rejection. Deposition of
complement membrane attack complex on ECs usually does not, by itself, kill ECs but may
induce endothelial microparticle (EMP) formation and thrombosis (see below) (87).
(7). Non-immune injuries
Hemodynamic factors combined with mediators such as cytokines have profound effects on
EC injury. Disturbances in flow patterns in atherosclerosis, post-surgical, intimal hyperplasia
and I/R injury or infection (e.g., with cytomegalovirus) can influence EC-T cell interactions
through expression of alarmins and adhesion molecules promoting rejection (88–90). These
responses may explain why renal allografts from living-related donors which are healthy,
generally have a higher graft survival than cadaver donor transplants, involving injured
kidneys.
(8). Thrombosis
Injury to ECs from whatever cause may lead to graft vessel thrombosis. Circulating
procoagulant EMPs, which are shed plasma membrane components, are markers of vascular
damage produced by EC apoptosis or deposition of the complement membrane attack complex,
but are also generated in response to thrombin, collagen, and/or shear stress (91,92). EMPs
impair EC function in vitro, diminishing acetylcholine-induced vasorelaxation and NO
production, and increasing superoxide production (93). At the same time, cytokine-activated
EC lose some anti-coagulant properties, such as expression of thrombomodulin and acquire
pro-coagulant properties such as expression of tissue factor and fibrinogen-like protein 2
(41). As noted earlier, EC injury and type II-activation may thus combine to promote
thrombosis.
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pathway of complement activation, which can be triggered by ischemia, could also lead to
endothelial C4d deposits. The diagnosis of AMR is supported by detection of circulating
antibodies that recognize graft ECs (54). Such antibodies most often react with HLA-A, B, C
and DR antigens, but circulating anti-EC antibodies that react with non-HLA alloantigens have
been detected in patients (80). Some non-HLA alloantigens are shared by ECs and monocytes
but not lymphocytes (E-M antigens), and some are only found on ECs (E antigens). MICA on
renal endothelium is also a potential target for AMR. AMR to ECs may involve complement
and complement-induced inflammation and/or NK cells, which recognize bound antibodies
via Fc receptor and mediate ADCC (81).
In addition to killing ECs via complement activation or targeting NK cells for ADCC,
alloantibodies may activate ECs. Anti-MHC antibodies activate ECs to degranulate Weibel-
Palade bodies, leading to release of IL-8 and display of P-selectin. In culture and in humans
skin grafts placed on immunodeficient mice, F(ab)’ fragments of an HLA-A,B,C antibody can
exert such effects despite their inability to engage Fc receptors or active complement (82).
Anti-class I antibodies may also be mitogenic for ECs, although the role of this response to
allograft rejection is unclear. Activation of the complement system may also affect ECs
independent of antibody, causing perturbation in EC barrier function retraction of EC plasma
membrane from the underlying substrate, release of preformed von Willebrand factor and P-
selectin from Weibel-Palade bodies to the cell surface, and production of cytokines including
IL-α, IL-8 and MCP-1 (83). The combination of C5a and antibody binding can cause ECs to
shed anti-coagulant heparan sulfates (84). ECs express a variety of complement receptors and
complement regulatory proteins that may modulate these responses (85,86). There is little
evidence to date that any of these are actively regulated in allograft rejection. Deposition of
complement membrane attack complex on ECs usually does not, by itself, kill ECs but may
induce endothelial microparticle (EMP) formation and thrombosis (see below) (87).
(7). Non-immune injuries
Hemodynamic factors combined with mediators such as cytokines have profound effects on
EC injury. Disturbances in flow patterns in atherosclerosis, post-surgical, intimal hyperplasia
and I/R injury or infection (e.g., with cytomegalovirus) can influence EC-T cell interactions
through expression of alarmins and adhesion molecules promoting rejection (88–90). These
responses may explain why renal allografts from living-related donors which are healthy,
generally have a higher graft survival than cadaver donor transplants, involving injured
kidneys.
(8). Thrombosis
Injury to ECs from whatever cause may lead to graft vessel thrombosis. Circulating
procoagulant EMPs, which are shed plasma membrane components, are markers of vascular
damage produced by EC apoptosis or deposition of the complement membrane attack complex,
but are also generated in response to thrombin, collagen, and/or shear stress (91,92). EMPs
impair EC function in vitro, diminishing acetylcholine-induced vasorelaxation and NO
production, and increasing superoxide production (93). At the same time, cytokine-activated
EC lose some anti-coagulant properties, such as expression of thrombomodulin and acquire
pro-coagulant properties such as expression of tissue factor and fibrinogen-like protein 2
(41). As noted earlier, EC injury and type II-activation may thus combine to promote
thrombosis.
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ECs Resistance to Injury and Repair
ECs can acquire resistance to injury by up-regulating a number of cytoprotective genes such
as hemoxygenase-1 (HO-1), A20, Bcl-2, and Bcl-x
L
, which protect cells from cytokine-
mediated apoptosis (94). Many of these gene products are regulated by NF-κB and are induced
by TNF. Induction of protective genes may contribute to resistance against AMR, a
phenomenon called “accommodation.” (94). Accommodated grafts function without rejection
despite the presence of recipient-specific antibodies. Although many genes contributing to
resistance to injury are regulated by NF-κB, activation of the serine/threonine kinase Akt via
the PI3K signaling pathway and/or of ERK-1,2 in response to TNF (95) or growth factors,
(96–98) can also contribute to cytoprotection. IL-11 and IL-6, which signal via STAT3, have
also been shown to render EC resistant to immune-mediated injury (99,100).
Graft vessels containing injured ECs may undergo repair. For injuries of limited extent,
neighboring ECs may simply spread to cover the defect and then divide. In cases of more
extensive vessel injury (e.g., vascular rejection), vessels of transplant recipients may display
endothelial chimerism through replacement of damaged donor endothelium by host-derived
precursors (101). The percentage of recipient ECs in the peritubular capillaries correlates with
the type of renal transplant rejection, being predominantly found in vascular rejection. It is
likely that ECs are lost from the vessel as a result of rejection and are replaced by circulating
endothelial progenitor cells (EPCs) that have the capacity to differentiate into mature ECs. The
markers that define circulating EPCs are controversial and true EPCs must be distinguished
from hematopoietic cells that stimulate angiogenesis but do not give rise to long-lived ECs
(102). The signals that recruit EPCs are also unknown, but both VEGF (103) and SDF-1
(104) are thought to be important. Both may be detected in allografts.
Conclusions
We have reviewed evidence that graft ECs are critical players in all stages of the host response
to allografts, contributing to the initiation and effector phases of rejection. We have also noted
that ECs may resist injury or contribute to repair. Despite these central roles performed by ECs,
it is striking that none of the existing therapeutic strategies to improve the outcome of
transplantation have focused on improving EC health or function. Development of such
strategies may not only protect the graft, but may also improve the cardiovascular health of the
host, a major complication of current transplantation medicine.
Acknowledgements
Supported by grants from National Institute for Health Research and British Heart Foundation to JRB and grants from
the NIH (HL036003, HL051014, HL062188 and HL070295) to JSP.
Abbreviations
ACR, acute cell-mediated rejection
ADCC, antibody-dependent cell-mediated cytotoxicity
AIF, apoptosis inducing factor
AMR, antibody-mediated rejection
APC, antigen presenting cell(s)
APAF-1, apoptotic protease activating factor-1
CTL, cytolytic T cell(s)
DC, dendritic cell(s)
DD, death domain
DR, death receptor
EC, endothelial cell(s)
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ECs can acquire resistance to injury by up-regulating a number of cytoprotective genes such
as hemoxygenase-1 (HO-1), A20, Bcl-2, and Bcl-x
L
, which protect cells from cytokine-
mediated apoptosis (94). Many of these gene products are regulated by NF-κB and are induced
by TNF. Induction of protective genes may contribute to resistance against AMR, a
phenomenon called “accommodation.” (94). Accommodated grafts function without rejection
despite the presence of recipient-specific antibodies. Although many genes contributing to
resistance to injury are regulated by NF-κB, activation of the serine/threonine kinase Akt via
the PI3K signaling pathway and/or of ERK-1,2 in response to TNF (95) or growth factors,
(96–98) can also contribute to cytoprotection. IL-11 and IL-6, which signal via STAT3, have
also been shown to render EC resistant to immune-mediated injury (99,100).
Graft vessels containing injured ECs may undergo repair. For injuries of limited extent,
neighboring ECs may simply spread to cover the defect and then divide. In cases of more
extensive vessel injury (e.g., vascular rejection), vessels of transplant recipients may display
endothelial chimerism through replacement of damaged donor endothelium by host-derived
precursors (101). The percentage of recipient ECs in the peritubular capillaries correlates with
the type of renal transplant rejection, being predominantly found in vascular rejection. It is
likely that ECs are lost from the vessel as a result of rejection and are replaced by circulating
endothelial progenitor cells (EPCs) that have the capacity to differentiate into mature ECs. The
markers that define circulating EPCs are controversial and true EPCs must be distinguished
from hematopoietic cells that stimulate angiogenesis but do not give rise to long-lived ECs
(102). The signals that recruit EPCs are also unknown, but both VEGF (103) and SDF-1
(104) are thought to be important. Both may be detected in allografts.
Conclusions
We have reviewed evidence that graft ECs are critical players in all stages of the host response
to allografts, contributing to the initiation and effector phases of rejection. We have also noted
that ECs may resist injury or contribute to repair. Despite these central roles performed by ECs,
it is striking that none of the existing therapeutic strategies to improve the outcome of
transplantation have focused on improving EC health or function. Development of such
strategies may not only protect the graft, but may also improve the cardiovascular health of the
host, a major complication of current transplantation medicine.
Acknowledgements
Supported by grants from National Institute for Health Research and British Heart Foundation to JRB and grants from
the NIH (HL036003, HL051014, HL062188 and HL070295) to JSP.
Abbreviations
ACR, acute cell-mediated rejection
ADCC, antibody-dependent cell-mediated cytotoxicity
AIF, apoptosis inducing factor
AMR, antibody-mediated rejection
APC, antigen presenting cell(s)
APAF-1, apoptotic protease activating factor-1
CTL, cytolytic T cell(s)
DC, dendritic cell(s)
DD, death domain
DR, death receptor
EC, endothelial cell(s)
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EMP, EC-derived microparticles
EPC, endothelial progenitor cell(s)
HO, hemoxygenase
ICAM-1, intercellular adhesion molecule-1
IL, interleukin
MCP-1, monocyte chemoattractant protein-I
MICA-1, MHC class I-related antigen A-1
NK, natural killer
ROS, reactive oxygen species
SMAC, second mediator of apoptotic cell death
TL1A, TNF-like molecule 1A
TNF, tumor necrosis factor
TNFR, TNF receptor
TRAIL, TNF-related apoptosis-inducing ligand
VCAM-1, vascular cell adhesion molecule-1
x-IAP, X-linked inhibitor of apoptosis protein
References
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2. Felix NJ, Allen PM. Specificity of T-cell alloreactivity. Nat Rev Immunol 2007;7:942. [PubMed:
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3. Lombardi G, Sidhu S, Daly M, Batchelor JR, Makgoba W, Lechler RI. Are primary alloresponses truly
primary? Int Immunol 1990;2:9. [PubMed: 1708274]
4. Epperson DE, Pober JS. Antigen-presenting function of human endothelial cells. Direct activation of
resting CD8 T cells. J Immunol 1994;153:5402. [PubMed: 7989746]
5. de Jong R, Brouwer M, Miedema F, van Lier RA. Human CD8+ T lymphocytes can be divided into
CD45RA+ and CD45RO+ cells with different requirements for activation and differentiation. J
Immunol 1991;146:2088. [PubMed: 1826015]
6. de Jong R, Brouwer M, Kuiper HM, Hooibrink B, Miedema F, van Lier RA. Maturation- and
differentiation-dependent responsiveness of human CD4+ T helper subsets. J Immunol
1992;149:2795. [PubMed: 1328387]
7. Shiao SL, McNiff JM, Pober JS. Memory T cells and their costimulators in human allograft injury. J
Immunol 2005;175:4886. [PubMed: 16210590]
8. Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr
Opin Immunol 2005;17:326. [PubMed: 15886125]
9. London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory
CD4+ T cells. J Immunol 2000;164:265. [PubMed: 10605020]
10. Yang J, Brook MO, Carvalho-Gaspar M, et al. Allograft rejection mediated by memory T cells is
resistant to regulation. Proc Natl Acad Sci U S A 2007;104:19954. [PubMed: 18042727]
11. Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant frequency of donor-specific, IFN-
gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the
risk of posttransplant rejection episodes. J Immunol 1999;163:2267. [PubMed: 10438971]
12. Kabelitz D, Medzhitov R. Innate immunity--cross-talk with adaptive immunity through pattern
recognition receptors and cytokines. Curr Opin Immunol 2007;19:1. [PubMed: 17157490]
13. Oppenheim JJ, Tewary P, de la Rosa G, Yang D. Alarmins initiate host defense. Adv Exp Med Biol
2007;601:185. [PubMed: 17713005]
14. Rao DA, Tracey KJ, Pober JS. IL-1alpha and IL-1beta are endogenous mediators linking cell injury
to the adaptive alloimmune response. J Immunol 2007;179:6536. [PubMed: 17982042]
15. Lechler RI, Batchelor JR. Restoration of immunogenicity to passenger cell-depleted kidney allografts
by the addition of donor strain dendritic cells. J Exp Med 1982;155:31. [PubMed: 7033437]
Al-Lamki et al. Page 8
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EPC, endothelial progenitor cell(s)
HO, hemoxygenase
ICAM-1, intercellular adhesion molecule-1
IL, interleukin
MCP-1, monocyte chemoattractant protein-I
MICA-1, MHC class I-related antigen A-1
NK, natural killer
ROS, reactive oxygen species
SMAC, second mediator of apoptotic cell death
TL1A, TNF-like molecule 1A
TNF, tumor necrosis factor
TNFR, TNF receptor
TRAIL, TNF-related apoptosis-inducing ligand
VCAM-1, vascular cell adhesion molecule-1
x-IAP, X-linked inhibitor of apoptosis protein
References
1. Game DS, Lechler RI. Pathways of allorecognition: implications for transplantation tolerance. Transpl
Immunol 2002;10:101. [PubMed: 12216939]
2. Felix NJ, Allen PM. Specificity of T-cell alloreactivity. Nat Rev Immunol 2007;7:942. [PubMed:
18007679]
3. Lombardi G, Sidhu S, Daly M, Batchelor JR, Makgoba W, Lechler RI. Are primary alloresponses truly
primary? Int Immunol 1990;2:9. [PubMed: 1708274]
4. Epperson DE, Pober JS. Antigen-presenting function of human endothelial cells. Direct activation of
resting CD8 T cells. J Immunol 1994;153:5402. [PubMed: 7989746]
5. de Jong R, Brouwer M, Miedema F, van Lier RA. Human CD8+ T lymphocytes can be divided into
CD45RA+ and CD45RO+ cells with different requirements for activation and differentiation. J
Immunol 1991;146:2088. [PubMed: 1826015]
6. de Jong R, Brouwer M, Kuiper HM, Hooibrink B, Miedema F, van Lier RA. Maturation- and
differentiation-dependent responsiveness of human CD4+ T helper subsets. J Immunol
1992;149:2795. [PubMed: 1328387]
7. Shiao SL, McNiff JM, Pober JS. Memory T cells and their costimulators in human allograft injury. J
Immunol 2005;175:4886. [PubMed: 16210590]
8. Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr
Opin Immunol 2005;17:326. [PubMed: 15886125]
9. London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory
CD4+ T cells. J Immunol 2000;164:265. [PubMed: 10605020]
10. Yang J, Brook MO, Carvalho-Gaspar M, et al. Allograft rejection mediated by memory T cells is
resistant to regulation. Proc Natl Acad Sci U S A 2007;104:19954. [PubMed: 18042727]
11. Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant frequency of donor-specific, IFN-
gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the
risk of posttransplant rejection episodes. J Immunol 1999;163:2267. [PubMed: 10438971]
12. Kabelitz D, Medzhitov R. Innate immunity--cross-talk with adaptive immunity through pattern
recognition receptors and cytokines. Curr Opin Immunol 2007;19:1. [PubMed: 17157490]
13. Oppenheim JJ, Tewary P, de la Rosa G, Yang D. Alarmins initiate host defense. Adv Exp Med Biol
2007;601:185. [PubMed: 17713005]
14. Rao DA, Tracey KJ, Pober JS. IL-1alpha and IL-1beta are endogenous mediators linking cell injury
to the adaptive alloimmune response. J Immunol 2007;179:6536. [PubMed: 17982042]
15. Lechler RI, Batchelor JR. Restoration of immunogenicity to passenger cell-depleted kidney allografts
by the addition of donor strain dendritic cells. J Exp Med 1982;155:31. [PubMed: 7033437]
Al-Lamki et al. Page 8
Transplantation. Author manuscript; available in PMC 2009 November 27.
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16. Lakkis FG, Arakelov A, Konieczny BT, Inoue Y. Immunologic 'ignorance' of vascularized organ
transplants in the absence of secondary lymphoid tissue. Nat Med 2000;6:686. [PubMed: 10835686]
17. Chalasani G, Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. Recall and propagation of allospecific
memory T cells independent of secondary lymphoid organs. Proc Natl Acad Sci U S A 2002;99:6175.
[PubMed: 11983909]
18. Kreisel D, Krupnick AS, Gelman AE, et al. Non-hematopoietic allograft cells directly activate CD8
+ T cells and trigger acute rejection: an alternative mechanism of allorecognition. Nat Med
2002;8:233. [PubMed: 11875493]
19. Brewer Y, Palmer A, Taube D, et al. Effect of graft perfusion with two CD45 monoclonal antibodies
on incidence of kidney allograft rejection. Lancet 1989;2:935. [PubMed: 2571860]
20. Hart DN, Fuggle SV, Williams KA, Fabre JW, Ting A, Morris PJ. Localization of HLA-ABC and
DR antigens in human kidney. Transplantation 1981;31:428. [PubMed: 6789507]
21. Hancock WW, Kraft N, Atkins RC. The immunohistochemical demonstration of major
histocompatibility antigens in the human kidney using monoclonal antibodies. Pathology
1982;14:409. [PubMed: 6760089]
22. Lapierre LA, Fiers W, Pober JS. Three distinct classes of regulatory cytokines control endothelial
cell MHC antigen expression. Interactions with immune gamma interferon differentiate the effects
of tumor necrosis factor and lymphotoxin from those of leukocyte alpha and fibroblast beta
interferons. J Exp Med 1988;167:794. [PubMed: 2450953]
23. Savage CO, Brooks CJ, Harcourt GC, et al. Human vascular endothelial cells process and present
autoantigen to human T cell lines. Int Immunol 1995;7:471. [PubMed: 7540863]
24. Kummer M, Lev A, Reiter Y, Biedermann BC. Vascular endothelial cells have impaired capacity to
present immunodominant, antigenic peptides: a mechanism of cell type-specific immune escape. J
Immunol 2005;174:1947. [PubMed: 15699122]
25. Biedermann BC, Pober JS. Human endothelial cells induce and regulate cytolytic T cell
differentiation. J Immunol 1998;161:4679. [PubMed: 9794397]
26. Dengler TJ, Pober JS. Human vascular endothelial cells stimulate memory but not naive CD8+ T
cells to differentiate into CTL retaining an early activation phenotype. J Immunol 2000;164:5146.
[PubMed: 10799873]
27. Hughes CC, Savage CO, Pober JS. Endothelial cells augment T cell interleukin 2 production by a
contact-dependent mechanism involving CD2/LFA-3 interaction. J Exp Med 1990;171:1453.
[PubMed: 1692079]
28. Pober JS, Collins T, Gimbrone MA Jr, et al. Lymphocytes recognize human vascular endothelial and
dermal fibroblast Ia antigens induced by recombinant immune interferon. Nature 1983;305:726.
[PubMed: 6415484]
29. Shiao SL, Kirkiles-Smith NC, Shepherd BR, McNiff JM, Carr EJ, Pober JS. Human effector memory
CD4+ T cells directly recognize allogeneic endothelial cells in vitro and in vivo. J Immunol
2007;179:4397. [PubMed: 17878335]
30. Biedermann BC, Pober JS. Human endothelial cells induce and regulate cytolytic T cell
differentiation. J.Immunol 1998;161:4679. [PubMed: 9794397]
31. Kreisel D, Krupnick AS, Balsara KR, et al. Mouse vascular endothelium activates CD8+ T
lymphocytes in a B7-dependent fashion. J Immunol 2002;169:6154. [PubMed: 12444119]
32. Kreisel D, Krasinskas AM, Krupnick AS, et al. Vascular endothelium does not activate CD4+ direct
allorecognition in graft rejection. J Immunol 2004;173:3027. [PubMed: 15322162]
33. Krupnick AS, Gelman AE, Barchet W, et al. Murine vascular endothelium activates and induces the
generation of allogeneic CD4+25+Foxp3+ regulatory T cells. J Immunol 2005;175:6265. [PubMed:
16272276]
34. Denton MD, Geehan CS, Alexander SI, Sayegh MH, Briscoe DM. Endothelial cells modify the
costimulatory capacity of transmigrating leukocytes and promote CD28-mediated CD4(+) T cell
alloactivation. J Exp Med 1999;190:555. [PubMed: 10449526]
35. Randolph GJ, Beaulieu S, Lebecque S, Steinman RM, Muller WA. Differentiation of monocytes into
dendritic cells in a model of transendothelial trafficking. Science 1998;282:480. [PubMed: 9774276]
Al-Lamki et al. Page 9
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transplants in the absence of secondary lymphoid tissue. Nat Med 2000;6:686. [PubMed: 10835686]
17. Chalasani G, Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. Recall and propagation of allospecific
memory T cells independent of secondary lymphoid organs. Proc Natl Acad Sci U S A 2002;99:6175.
[PubMed: 11983909]
18. Kreisel D, Krupnick AS, Gelman AE, et al. Non-hematopoietic allograft cells directly activate CD8
+ T cells and trigger acute rejection: an alternative mechanism of allorecognition. Nat Med
2002;8:233. [PubMed: 11875493]
19. Brewer Y, Palmer A, Taube D, et al. Effect of graft perfusion with two CD45 monoclonal antibodies
on incidence of kidney allograft rejection. Lancet 1989;2:935. [PubMed: 2571860]
20. Hart DN, Fuggle SV, Williams KA, Fabre JW, Ting A, Morris PJ. Localization of HLA-ABC and
DR antigens in human kidney. Transplantation 1981;31:428. [PubMed: 6789507]
21. Hancock WW, Kraft N, Atkins RC. The immunohistochemical demonstration of major
histocompatibility antigens in the human kidney using monoclonal antibodies. Pathology
1982;14:409. [PubMed: 6760089]
22. Lapierre LA, Fiers W, Pober JS. Three distinct classes of regulatory cytokines control endothelial
cell MHC antigen expression. Interactions with immune gamma interferon differentiate the effects
of tumor necrosis factor and lymphotoxin from those of leukocyte alpha and fibroblast beta
interferons. J Exp Med 1988;167:794. [PubMed: 2450953]
23. Savage CO, Brooks CJ, Harcourt GC, et al. Human vascular endothelial cells process and present
autoantigen to human T cell lines. Int Immunol 1995;7:471. [PubMed: 7540863]
24. Kummer M, Lev A, Reiter Y, Biedermann BC. Vascular endothelial cells have impaired capacity to
present immunodominant, antigenic peptides: a mechanism of cell type-specific immune escape. J
Immunol 2005;174:1947. [PubMed: 15699122]
25. Biedermann BC, Pober JS. Human endothelial cells induce and regulate cytolytic T cell
differentiation. J Immunol 1998;161:4679. [PubMed: 9794397]
26. Dengler TJ, Pober JS. Human vascular endothelial cells stimulate memory but not naive CD8+ T
cells to differentiate into CTL retaining an early activation phenotype. J Immunol 2000;164:5146.
[PubMed: 10799873]
27. Hughes CC, Savage CO, Pober JS. Endothelial cells augment T cell interleukin 2 production by a
contact-dependent mechanism involving CD2/LFA-3 interaction. J Exp Med 1990;171:1453.
[PubMed: 1692079]
28. Pober JS, Collins T, Gimbrone MA Jr, et al. Lymphocytes recognize human vascular endothelial and
dermal fibroblast Ia antigens induced by recombinant immune interferon. Nature 1983;305:726.
[PubMed: 6415484]
29. Shiao SL, Kirkiles-Smith NC, Shepherd BR, McNiff JM, Carr EJ, Pober JS. Human effector memory
CD4+ T cells directly recognize allogeneic endothelial cells in vitro and in vivo. J Immunol
2007;179:4397. [PubMed: 17878335]
30. Biedermann BC, Pober JS. Human endothelial cells induce and regulate cytolytic T cell
differentiation. J.Immunol 1998;161:4679. [PubMed: 9794397]
31. Kreisel D, Krupnick AS, Balsara KR, et al. Mouse vascular endothelium activates CD8+ T
lymphocytes in a B7-dependent fashion. J Immunol 2002;169:6154. [PubMed: 12444119]
32. Kreisel D, Krasinskas AM, Krupnick AS, et al. Vascular endothelium does not activate CD4+ direct
allorecognition in graft rejection. J Immunol 2004;173:3027. [PubMed: 15322162]
33. Krupnick AS, Gelman AE, Barchet W, et al. Murine vascular endothelium activates and induces the
generation of allogeneic CD4+25+Foxp3+ regulatory T cells. J Immunol 2005;175:6265. [PubMed:
16272276]
34. Denton MD, Geehan CS, Alexander SI, Sayegh MH, Briscoe DM. Endothelial cells modify the
costimulatory capacity of transmigrating leukocytes and promote CD28-mediated CD4(+) T cell
alloactivation. J Exp Med 1999;190:555. [PubMed: 10449526]
35. Randolph GJ, Beaulieu S, Lebecque S, Steinman RM, Muller WA. Differentiation of monocytes into
dendritic cells in a model of transendothelial trafficking. Science 1998;282:480. [PubMed: 9774276]
Al-Lamki et al. Page 9
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36. Bagai R, Valujskikh A, Canaday DH, et al. Mouse endothelial cells cross-present lymphocyte-derived
antigen on class I MHC via a TAP1- and proteasome-dependent pathway. J Immunol 2005;174:7711.
[PubMed: 15944272]
37. Tellides G, Pober JS. Interferon-gamma axis in graft arteriosclerosis. Circ Res 2007;100:622.
[PubMed: 17363708]
38. Minami E, Laflamme MA, Saffitz JE, Murry CE. Extracardiac progenitor cells repopulate most major
cell types in the transplanted human heart. Circulation 2005;112:2951. [PubMed: 16275883]
39. Salomon RN, Hughes CC, Schoen FJ, Payne DD, Pober JS, Libby P. Human coronary transplantation-
associated arteriosclerosis. Evidence for a chronic immune reaction to activated graft endothelial
cells. Am J Pathol 1991;138:791. [PubMed: 2012171]
40. Choy JC, Wang Y, Tellides G, Pober JS. Induction of inducible NO synthase in bystander human T
cells increases allogeneic responses in the vasculature. Proc Natl Acad Sci U S A 2007;104:1313.
[PubMed: 17227851]
41. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol
2007;7:803. [PubMed: 17893694]
42. Grandaliano G, Gesualdo L, Ranieri E, Monno R, Stallone G, Schena FP. Monocyte chemotactic
peptide-1 expression and monocyte infiltration in acute renal transplant rejection. Transplantation
1997;63:414. [PubMed: 9039933]
43. Manes TD, Pober JS, Kluger MS. Endothelial cell-T lymphocyte interactions: IP-10 stimulates rapid
transendothelial migration of human effort but not central memory CD4+ T cells. Requirements for
shear stress and adhesion molecules. Transplantation 2006;82:S9. [PubMed: 16829798]
44. Imaizumi T, Albertine KH, Jicha DL, McIntyre TM, Prescott SM, Zimmerman GA. Human
endothelial cells synthesize ENA-78: relationship to IL-8 and to signaling of PMN adhesion. Am J
Respir Cell Mol Biol 1997;17:181. [PubMed: 9271306]
45. Panzer U, Reinking RR, Steinmetz OM, et al. CXCR3 and CCR5 positive T-cell recruitment in acute
human renal allograft rejection. Transplantation 2004;78:1341. [PubMed: 15548973]
46. Hoffmann U, Segerer S, Rummele P, et al. Expression of the chemokine receptor CXCR3 in human
renal allografts--a prospective study. Nephrol Dial Transplant 2006;21:1373. [PubMed: 16421159]
47. Cinamon G, Shinder V, Alon R. Shear forces promote lymphocyte migration across vascular
endothelium bearing apical chemokines. Nat Immunol 2001;2:515. [PubMed: 11376338]
48. Carman CV, Springer TA. A transmigratory cup in leukocyte diapedesis both through individual
vascular endothelial cells and between them. J Cell Biol 2004;167:377. [PubMed: 15504916]
49. Karmann K, Hughes CC, Schechner J, Fanslow WC, Pober JS. CD40 on human endothelial cells:
inducibility by cytokines and functional regulation of adhesion molecule expression. Proc Natl Acad
Sci U S A 1995;92:4342. [PubMed: 7538666]
50. Manes T, Pober JS. Antigen presentation by human microvascular endothelial cells triggers ICAM-1-
independent transndothelial protrusion by and factalkine-dependent transendothelial migration of
effector memory CD4+ T cells. J Immunol. 2008(in press)
51. Manes TD, Pober JS, Kluger MS. Endothelial cell-T lymphocyte interactions: IP[corrected]-10
stimulates rapid transendothelial migration of human effort but not central memory CD4+ T cells.
Requirements for shear stress and adhesion molecules. Transplantation 2006;82:S9. [PubMed:
16829798]
52. Shimizu A, Colvin RB. Pathological features of antibody-mediated rejection. Curr Drug Targets
Cardiovasc Haematol Disord 2005;5:199. [PubMed: 15975034]
53. Meehan SM, McCluskey RT, Pascual M, et al. Cytotoxicity and apoptosis in human renal allografts:
identification, distribution, and quantitation of cells with a cytotoxic granule protein GMP-17 (TIA-1)
and cells with fragmented nuclear DNA. Lab Invest 1997;76:639. [PubMed: 9166283]
54. Colvin RB, Cohen AH, Saiontz C, et al. Evaluation of pathologic criteria for acute renal allograft
rejection: reproducibility, sensitivity, and clinical correlation. J.Am.Soc.Nephrol 1997;8:1930.
[PubMed: 9402096]
55. Strehlau J, Pavlakis M, Lipman M, et al. Quantitative detection of immune activation transcripts as
a diagnostic tool in kidney transplantation. Proc.Natl.Acad.Sci.U.S.A 1997;94:695. [PubMed:
9012847]
Al-Lamki et al. Page 10
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antigen on class I MHC via a TAP1- and proteasome-dependent pathway. J Immunol 2005;174:7711.
[PubMed: 15944272]
37. Tellides G, Pober JS. Interferon-gamma axis in graft arteriosclerosis. Circ Res 2007;100:622.
[PubMed: 17363708]
38. Minami E, Laflamme MA, Saffitz JE, Murry CE. Extracardiac progenitor cells repopulate most major
cell types in the transplanted human heart. Circulation 2005;112:2951. [PubMed: 16275883]
39. Salomon RN, Hughes CC, Schoen FJ, Payne DD, Pober JS, Libby P. Human coronary transplantation-
associated arteriosclerosis. Evidence for a chronic immune reaction to activated graft endothelial
cells. Am J Pathol 1991;138:791. [PubMed: 2012171]
40. Choy JC, Wang Y, Tellides G, Pober JS. Induction of inducible NO synthase in bystander human T
cells increases allogeneic responses in the vasculature. Proc Natl Acad Sci U S A 2007;104:1313.
[PubMed: 17227851]
41. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol
2007;7:803. [PubMed: 17893694]
42. Grandaliano G, Gesualdo L, Ranieri E, Monno R, Stallone G, Schena FP. Monocyte chemotactic
peptide-1 expression and monocyte infiltration in acute renal transplant rejection. Transplantation
1997;63:414. [PubMed: 9039933]
43. Manes TD, Pober JS, Kluger MS. Endothelial cell-T lymphocyte interactions: IP-10 stimulates rapid
transendothelial migration of human effort but not central memory CD4+ T cells. Requirements for
shear stress and adhesion molecules. Transplantation 2006;82:S9. [PubMed: 16829798]
44. Imaizumi T, Albertine KH, Jicha DL, McIntyre TM, Prescott SM, Zimmerman GA. Human
endothelial cells synthesize ENA-78: relationship to IL-8 and to signaling of PMN adhesion. Am J
Respir Cell Mol Biol 1997;17:181. [PubMed: 9271306]
45. Panzer U, Reinking RR, Steinmetz OM, et al. CXCR3 and CCR5 positive T-cell recruitment in acute
human renal allograft rejection. Transplantation 2004;78:1341. [PubMed: 15548973]
46. Hoffmann U, Segerer S, Rummele P, et al. Expression of the chemokine receptor CXCR3 in human
renal allografts--a prospective study. Nephrol Dial Transplant 2006;21:1373. [PubMed: 16421159]
47. Cinamon G, Shinder V, Alon R. Shear forces promote lymphocyte migration across vascular
endothelium bearing apical chemokines. Nat Immunol 2001;2:515. [PubMed: 11376338]
48. Carman CV, Springer TA. A transmigratory cup in leukocyte diapedesis both through individual
vascular endothelial cells and between them. J Cell Biol 2004;167:377. [PubMed: 15504916]
49. Karmann K, Hughes CC, Schechner J, Fanslow WC, Pober JS. CD40 on human endothelial cells:
inducibility by cytokines and functional regulation of adhesion molecule expression. Proc Natl Acad
Sci U S A 1995;92:4342. [PubMed: 7538666]
50. Manes T, Pober JS. Antigen presentation by human microvascular endothelial cells triggers ICAM-1-
independent transndothelial protrusion by and factalkine-dependent transendothelial migration of
effector memory CD4+ T cells. J Immunol. 2008(in press)
51. Manes TD, Pober JS, Kluger MS. Endothelial cell-T lymphocyte interactions: IP[corrected]-10
stimulates rapid transendothelial migration of human effort but not central memory CD4+ T cells.
Requirements for shear stress and adhesion molecules. Transplantation 2006;82:S9. [PubMed:
16829798]
52. Shimizu A, Colvin RB. Pathological features of antibody-mediated rejection. Curr Drug Targets
Cardiovasc Haematol Disord 2005;5:199. [PubMed: 15975034]
53. Meehan SM, McCluskey RT, Pascual M, et al. Cytotoxicity and apoptosis in human renal allografts:
identification, distribution, and quantitation of cells with a cytotoxic granule protein GMP-17 (TIA-1)
and cells with fragmented nuclear DNA. Lab Invest 1997;76:639. [PubMed: 9166283]
54. Colvin RB, Cohen AH, Saiontz C, et al. Evaluation of pathologic criteria for acute renal allograft
rejection: reproducibility, sensitivity, and clinical correlation. J.Am.Soc.Nephrol 1997;8:1930.
[PubMed: 9402096]
55. Strehlau J, Pavlakis M, Lipman M, et al. Quantitative detection of immune activation transcripts as
a diagnostic tool in kidney transplantation. Proc.Natl.Acad.Sci.U.S.A 1997;94:695. [PubMed:
9012847]
Al-Lamki et al. Page 10
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56. Jutte NH, Knoop CJ, Heijse P, et al. Human heart endothelial-cell-restricted allorecognition.
Transplantation 1996;62:403. [PubMed: 8779690]
57. Bleackley RC. A molecular view of cytotoxicT lymphocyte induced killing. Biochem Cell Biol
2005;83:747. [PubMed: 16333326]
58. Zheng L, Dengler TJ, Kluger MS, et al. Cytoprotection of human umbilical vein endothelial cells
against apoptosis and CTL-mediated lysis provided by caspase-resistant Bcl-2 without alterations in
growth or activation responses. J Immunol 2000;164:4665. [PubMed: 10779771]
59. Hsieh CL, Obara H, Ogura Y, Martinez OM, Krams SM. NK cells and transplantation.
Transpl.Immunol 2002;9:111. [PubMed: 12180816]
60. Bottino C, Moretta L, Pende D, Vitale M, Moretta A. Learning how to discriminate between friends
and enemies, a lesson from Natural Killer cells. Mol.Immunol 2004;41:569. [PubMed: 15219995]
61. Bender JR, Pardi R, Engleman E. T-cell receptor-negative natural killer cells display antigen-specific
cytotoxicity for microvascular endothelial cells. Proc Natl Acad Sci U S A 1990;87:6949. [PubMed:
2402485]
62. Candinas D, Belliveau S, Koyamada N, et al. T cell independence of macrophage and natural killer
cell infiltration, cytokine production, and endothelial activation during delayed xenograft rejection.
Transplantation 1996;62:1920. [PubMed: 8990388]
63. Uehara S, Chase CM, Kitchens WH, et al. NK cells can trigger allograft vasculopathy: the role of
hybrid resistance in solid organ allografts. J Immunol 2005;175:3424. [PubMed: 16116237]
64. Wyburn KR, Jose MD, Wu H, Atkins RC, Chadban SJ. The role of macrophages in allograft rejection.
Transplantation 2005;80:1641. [PubMed: 16378052]
65. Diez-Roux G, Lang RA. Macrophages induce apoptosis in normal cells in vivo. Development
1997;124:3633. [PubMed: 9342055]
66. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci
2008;13:453. [PubMed: 17981560]
67. Briscoe DM, Schoen FJ, Rice GE, Bevilacqua MP, Ganz P, Pober JS. Induced expression of
endothelial-leukocyte adhesion molecules in human cardiac allografts. Transplantation 1991;51:537.
[PubMed: 1704649]
68. Ferran C, Peuchmaur M, Desruennes M, et al. Implications of de novo ELAM-1 and VCAM-1
expression in human cardiac allograft rejection. Transplantation 1993;55:605. [PubMed: 7681227]
69. Morita K, Miura M, Paolone DR, et al. Early chemokine cascades in murine cardiac grafts regulate
T cell recruitment and progression of acute allograft rejection. J Immunol 2001;167:2979. [PubMed:
11509648]
70. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305.
[PubMed: 9721089]
71. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating
mammalian biology. Cell 2001;104:487. [PubMed: 11239407]
72. Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions
as a T cell costimulator. Immunity 2002;16:479. [PubMed: 11911831]
73. Al-Lamki RS, Wang J, Tolkovsky AM, et al. TL1A Both Promotes and Protects from Renal
Inflammation and Injury. J.Am.Soc.Nephrol. 2008(Epub ahead of print)
74. Li JH, Kluger MS, Madge LA, Zheng L, Bothwell AL, Pober JS. Interferon-gamma augments CD95
(APO-1/Fas) and pro-caspase-8 expression and sensitizes human vascular endothelial cells to CD95-
mediated apoptosis. Am J Pathol 2002;161:1485. [PubMed: 12368221]
75. Li JH, Pober JS. The cathepsin B death pathway contributes to TNF plus IFN-gamma-mediated human
endothelial injury. J Immunol 2005;175:1858. [PubMed: 16034129]
76. Al-Lamki RS, Wang J, Skepper JN, Thiru S, Pober JS, Bradley JR. Expression of tumor necrosis
factor receptors in normal kidney and rejecting renal transplants. Lab Invest 2001;81:1503. [PubMed:
11706058]
77. Al-Lamki RS, Wang J, Thiru S, et al. Expression of silencer of death domains and death-receptor-3
in normal human kidney and in rejecting renal transplants. Am.J.Pathol 2003;163:401. [PubMed:
12875962]
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Transplantation 1996;62:403. [PubMed: 8779690]
57. Bleackley RC. A molecular view of cytotoxicT lymphocyte induced killing. Biochem Cell Biol
2005;83:747. [PubMed: 16333326]
58. Zheng L, Dengler TJ, Kluger MS, et al. Cytoprotection of human umbilical vein endothelial cells
against apoptosis and CTL-mediated lysis provided by caspase-resistant Bcl-2 without alterations in
growth or activation responses. J Immunol 2000;164:4665. [PubMed: 10779771]
59. Hsieh CL, Obara H, Ogura Y, Martinez OM, Krams SM. NK cells and transplantation.
Transpl.Immunol 2002;9:111. [PubMed: 12180816]
60. Bottino C, Moretta L, Pende D, Vitale M, Moretta A. Learning how to discriminate between friends
and enemies, a lesson from Natural Killer cells. Mol.Immunol 2004;41:569. [PubMed: 15219995]
61. Bender JR, Pardi R, Engleman E. T-cell receptor-negative natural killer cells display antigen-specific
cytotoxicity for microvascular endothelial cells. Proc Natl Acad Sci U S A 1990;87:6949. [PubMed:
2402485]
62. Candinas D, Belliveau S, Koyamada N, et al. T cell independence of macrophage and natural killer
cell infiltration, cytokine production, and endothelial activation during delayed xenograft rejection.
Transplantation 1996;62:1920. [PubMed: 8990388]
63. Uehara S, Chase CM, Kitchens WH, et al. NK cells can trigger allograft vasculopathy: the role of
hybrid resistance in solid organ allografts. J Immunol 2005;175:3424. [PubMed: 16116237]
64. Wyburn KR, Jose MD, Wu H, Atkins RC, Chadban SJ. The role of macrophages in allograft rejection.
Transplantation 2005;80:1641. [PubMed: 16378052]
65. Diez-Roux G, Lang RA. Macrophages induce apoptosis in normal cells in vivo. Development
1997;124:3633. [PubMed: 9342055]
66. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci
2008;13:453. [PubMed: 17981560]
67. Briscoe DM, Schoen FJ, Rice GE, Bevilacqua MP, Ganz P, Pober JS. Induced expression of
endothelial-leukocyte adhesion molecules in human cardiac allografts. Transplantation 1991;51:537.
[PubMed: 1704649]
68. Ferran C, Peuchmaur M, Desruennes M, et al. Implications of de novo ELAM-1 and VCAM-1
expression in human cardiac allograft rejection. Transplantation 1993;55:605. [PubMed: 7681227]
69. Morita K, Miura M, Paolone DR, et al. Early chemokine cascades in murine cardiac grafts regulate
T cell recruitment and progression of acute allograft rejection. J Immunol 2001;167:2979. [PubMed:
11509648]
70. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305.
[PubMed: 9721089]
71. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating
mammalian biology. Cell 2001;104:487. [PubMed: 11239407]
72. Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions
as a T cell costimulator. Immunity 2002;16:479. [PubMed: 11911831]
73. Al-Lamki RS, Wang J, Tolkovsky AM, et al. TL1A Both Promotes and Protects from Renal
Inflammation and Injury. J.Am.Soc.Nephrol. 2008(Epub ahead of print)
74. Li JH, Kluger MS, Madge LA, Zheng L, Bothwell AL, Pober JS. Interferon-gamma augments CD95
(APO-1/Fas) and pro-caspase-8 expression and sensitizes human vascular endothelial cells to CD95-
mediated apoptosis. Am J Pathol 2002;161:1485. [PubMed: 12368221]
75. Li JH, Pober JS. The cathepsin B death pathway contributes to TNF plus IFN-gamma-mediated human
endothelial injury. J Immunol 2005;175:1858. [PubMed: 16034129]
76. Al-Lamki RS, Wang J, Skepper JN, Thiru S, Pober JS, Bradley JR. Expression of tumor necrosis
factor receptors in normal kidney and rejecting renal transplants. Lab Invest 2001;81:1503. [PubMed:
11706058]
77. Al-Lamki RS, Wang J, Thiru S, et al. Expression of silencer of death domains and death-receptor-3
in normal human kidney and in rejecting renal transplants. Am.J.Pathol 2003;163:401. [PubMed:
12875962]
Al-Lamki et al. Page 11
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78. Al-Lamki RS, Wang J, Vandenabeele P, et al. TNFR1- and TNFR2-mediated signaling pathways in
human kidney are cell type-specific and differentially contribute to renal injury. FASEB J
2005;19:1637. [PubMed: 16195372]
79. Kato M, Morozumi K, Takeuchi O, et al. Complement fragment C4d deposition in peritubular
capillaries in acute humoral rejection after ABO blood group-incompatible human kidney
transplantation. Transplantation 2003;75:663. [PubMed: 12640306]
80. Tinckam KJ, Chandraker A. Mechanisms and role of HLA and non-HLA alloantibodies. Clin J Am
Soc Nephrol 2006;1:404. [PubMed: 17699239]
81. Akalin E, Watschinger B. Antibody-mediated rejection. Semin Nephrol 2007;27:393. [PubMed:
17616272]
82. Yamakuchi M, Kirkiles-Smith NC, Ferlito M, et al. Antibody to human leukocyte antigen triggers
endothelial exocytosis. Proc Natl Acad Sci U S A 2007;104:1301. [PubMed: 17229850]
83. Wasowska BA, Lee CY, Halushka MK, Baldwin WM 3rd. New concepts of complement in
allorecognition and graft rejection. Cell Immunol 2007;248:18. [PubMed: 17950717]
84. Platt JL, Dalmasso AP, Lindman BJ, Ihrcke NS, Bach FH. The role of C5a and antibody in the release
of heparan sulfate from endothelial cells. Eur J Immunol 1991;21:2887. [PubMed: 1936126]
85. Brooimans RA, van Wieringen PA, van Es LA, Daha MR. Relative roles of decayaccelerating factor,
membrane cofactor protein, and CD59 in the protection of human endothelial cells against
complement-mediated lysis. Eur.J.Immunol 1992;22:3135. [PubMed: 1280224]
86. Brooimans RA, Van der Ark AA, Tomita M, van Es LA, Daha MR. CD59 expressed by human
endothelial cells functions as a protective molecule against complement-mediated lysis.
Eur.J.Immunol 1992;22:791. [PubMed: 1372260]
87. Sims PJ, Wiedmer T. Induction of cellular procoagulant activity by the membrane attack complex of
complement. Semin Cell Biol 1995;6:275. [PubMed: 8562920]
88. Methe H, Balcells M, Alegret MC, et al. Vascular bed origin dictates flow pattern regulation of
endothelial adhesion molecule expression. Am.J.Physiol Heart Circ.Physiol 2007;292:H2167.
[PubMed: 17209004]
89. Koo DD, Welsh KI, McLaren AJ, Roake JA, Morris PJ, Fuggle SV. Cadaver versus living donor
kidneys: impact of donor factors on antigen induction before transplantation. Kidney Int
1999;56:1551. [PubMed: 10504507]
90. Schlichting CL, Schareck WD, Weis M. Renal ischemia-reperfusion injury: new implications of
dendritic cell-endothelial cell interactions. Transplant.Proc 2006;38:670. [PubMed: 16647440]
91. Brodsky SV, Zhang F, Nasjletti A, Goligorsky MS. Endothelium-derived microparticles impair
endothelial function in vitro. Am.J.Physiol Heart Circ.Physiol 2004;286:H1910. [PubMed:
15072974]
92. Densmore JC, Signorino PR, Ou J, et al. Endothelium-derived microparticles induce endothelial
dysfunction and acute lung injury. Shock 2006;26:464. [PubMed: 17047516]
93. Mezentsev A, Merks RM, O'Riordan E, et al. Endothelial microparticles affect angiogenesis in vitro:
role of oxidative stress. Am.J.Physiol Heart Circ.Physiol 2005;289:H1106. [PubMed: 15879485]
94. Soares MP, Lin Y, Sato K, Stuhlmeier KM, Bach FH. Accommodation. Immunol Today 1999;20:434.
[PubMed: 10500288]
95. Madge LA, Pober JS. A phosphatidylinositol 3-kinase/Akt pathway, activated by tumor necrosis
factor or interleukin-1, inhibits apoptosis but does not activate NFkappaB in human endothelial cells.
J Biol Chem 2000;275:15458. [PubMed: 10748004]
96. Lemos FB, Ijzermans JN, Zondervan PE, et al. Differential expression of heme oxygenase-1 and
vascular endothelial growth factor in cadaveric and living donor kidneys after ischemia-reperfusion.
J Am Soc Nephrol 2003;14:3278. [PubMed: 14638927]
97. House SL, Bolte C, Zhou M, et al. Cardiac-specific overexpression of fibroblast growth factor-2
protects against myocardial dysfunction and infarction in a murine model of low-flow ischemia.
Circulation 2003;108:3140. [PubMed: 14656920]
98. d'Uscio LV, Smith LA, Santhanam AV, Richardson D, Nath KA, Katusic ZS. Essential role of
endothelial nitric oxide synthase in vascular effects of erythropoietin. Hypertension 2007;49:1142.
[PubMed: 17372034]
Al-Lamki et al. Page 12
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human kidney are cell type-specific and differentially contribute to renal injury. FASEB J
2005;19:1637. [PubMed: 16195372]
79. Kato M, Morozumi K, Takeuchi O, et al. Complement fragment C4d deposition in peritubular
capillaries in acute humoral rejection after ABO blood group-incompatible human kidney
transplantation. Transplantation 2003;75:663. [PubMed: 12640306]
80. Tinckam KJ, Chandraker A. Mechanisms and role of HLA and non-HLA alloantibodies. Clin J Am
Soc Nephrol 2006;1:404. [PubMed: 17699239]
81. Akalin E, Watschinger B. Antibody-mediated rejection. Semin Nephrol 2007;27:393. [PubMed:
17616272]
82. Yamakuchi M, Kirkiles-Smith NC, Ferlito M, et al. Antibody to human leukocyte antigen triggers
endothelial exocytosis. Proc Natl Acad Sci U S A 2007;104:1301. [PubMed: 17229850]
83. Wasowska BA, Lee CY, Halushka MK, Baldwin WM 3rd. New concepts of complement in
allorecognition and graft rejection. Cell Immunol 2007;248:18. [PubMed: 17950717]
84. Platt JL, Dalmasso AP, Lindman BJ, Ihrcke NS, Bach FH. The role of C5a and antibody in the release
of heparan sulfate from endothelial cells. Eur J Immunol 1991;21:2887. [PubMed: 1936126]
85. Brooimans RA, van Wieringen PA, van Es LA, Daha MR. Relative roles of decayaccelerating factor,
membrane cofactor protein, and CD59 in the protection of human endothelial cells against
complement-mediated lysis. Eur.J.Immunol 1992;22:3135. [PubMed: 1280224]
86. Brooimans RA, Van der Ark AA, Tomita M, van Es LA, Daha MR. CD59 expressed by human
endothelial cells functions as a protective molecule against complement-mediated lysis.
Eur.J.Immunol 1992;22:791. [PubMed: 1372260]
87. Sims PJ, Wiedmer T. Induction of cellular procoagulant activity by the membrane attack complex of
complement. Semin Cell Biol 1995;6:275. [PubMed: 8562920]
88. Methe H, Balcells M, Alegret MC, et al. Vascular bed origin dictates flow pattern regulation of
endothelial adhesion molecule expression. Am.J.Physiol Heart Circ.Physiol 2007;292:H2167.
[PubMed: 17209004]
89. Koo DD, Welsh KI, McLaren AJ, Roake JA, Morris PJ, Fuggle SV. Cadaver versus living donor
kidneys: impact of donor factors on antigen induction before transplantation. Kidney Int
1999;56:1551. [PubMed: 10504507]
90. Schlichting CL, Schareck WD, Weis M. Renal ischemia-reperfusion injury: new implications of
dendritic cell-endothelial cell interactions. Transplant.Proc 2006;38:670. [PubMed: 16647440]
91. Brodsky SV, Zhang F, Nasjletti A, Goligorsky MS. Endothelium-derived microparticles impair
endothelial function in vitro. Am.J.Physiol Heart Circ.Physiol 2004;286:H1910. [PubMed:
15072974]
92. Densmore JC, Signorino PR, Ou J, et al. Endothelium-derived microparticles induce endothelial
dysfunction and acute lung injury. Shock 2006;26:464. [PubMed: 17047516]
93. Mezentsev A, Merks RM, O'Riordan E, et al. Endothelial microparticles affect angiogenesis in vitro:
role of oxidative stress. Am.J.Physiol Heart Circ.Physiol 2005;289:H1106. [PubMed: 15879485]
94. Soares MP, Lin Y, Sato K, Stuhlmeier KM, Bach FH. Accommodation. Immunol Today 1999;20:434.
[PubMed: 10500288]
95. Madge LA, Pober JS. A phosphatidylinositol 3-kinase/Akt pathway, activated by tumor necrosis
factor or interleukin-1, inhibits apoptosis but does not activate NFkappaB in human endothelial cells.
J Biol Chem 2000;275:15458. [PubMed: 10748004]
96. Lemos FB, Ijzermans JN, Zondervan PE, et al. Differential expression of heme oxygenase-1 and
vascular endothelial growth factor in cadaveric and living donor kidneys after ischemia-reperfusion.
J Am Soc Nephrol 2003;14:3278. [PubMed: 14638927]
97. House SL, Bolte C, Zhou M, et al. Cardiac-specific overexpression of fibroblast growth factor-2
protects against myocardial dysfunction and infarction in a murine model of low-flow ischemia.
Circulation 2003;108:3140. [PubMed: 14656920]
98. d'Uscio LV, Smith LA, Santhanam AV, Richardson D, Nath KA, Katusic ZS. Essential role of
endothelial nitric oxide synthase in vascular effects of erythropoietin. Hypertension 2007;49:1142.
[PubMed: 17372034]
Al-Lamki et al. Page 12
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99. Mahboubi K, Biedermann BC, Carroll JM, Pober JS, et al. IL-11 activates human endothelial cells
to resist immune-mediated injury. J Immunol 2000;164:3837. [PubMed: 10725745]
100. Waxman AB, Mahboubi K, Knickelbein RG, et al. Interleukin-11 and interleukin-6 protect cultured
human endothelial cells from H2O2-induced cell death. Am J Respir Cell Mol Biol 2003;29:513.
[PubMed: 12730073]
101. Lagaaij EL, Cramer-Knijnenburg GF, van Kemenade FJ, van Es LA, Bruijn JA, van Krieken JH.
Endothelial cell chimerism after renal transplantation and vascular rejection. Lancet 2001;357:33.
[PubMed: 11197359]
102. Sieveking DP, Buckle A, Celermajer DS, Ng MK. Strikingly different angiogenic properties of
endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay.
J.Am.Coll.Cardiol 2008;51:660. [PubMed: 18261686]
103. Wijelath ES, Rahman S, Murray J, Patel Y, Savidge G, Sobel M. Fibronectin promotes VEGF-
induced CD34 cell differentiation into endothelial cells. J.Vasc.Surg 2004;39:655. [PubMed:
14981463]
104. Zemani F, Silvestre JS, Fauvel-Lafeve F, et al. Ex vivo priming of endothelial progenitor cells with
SDF-1 before transplantation could increase their proangiogenic potential.
Arterioscler.Thromb.Vasc.Biol 2008;28:644. [PubMed: 18239152]
105. Min W, Pober JS, Johnson DR. Kinetically coordinated induction of TAP1 and HLA class I by IFN-
gamma: the rapid induction of TAP1 by IFN-gamma is mediated by Stat1 alpha. J Immunol
1996;156:3174. [PubMed: 8617938]
106. Collins T, Korman AJ, Wake CT, et al. Immune interferon activates multiple class II major
histocompatibility complex genes and the associated invariant chain gene in human endothelial
cells and dermal fibroblasts. Proc Natl Acad Sci U S A 1984;81:4917. [PubMed: 6431411]
107. Pober JS, Gimbrone MA Jr, Collins T, et al. Interactions of T lymphocytes with human vascular
endothelial cells: role of endothelial cells surface antigens. Immunobiology 1984;168:483.
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108. Suarez Y, Shepherd BR, Rao DA, Pober JS. Alloimmunity to human endothelial cells derived from
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111. Kurt-Jones EA, Fiers W, Pober JS. Membrane interleukin 1 induction on human endothelial cells
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113. Beutelspacher SC, Tan PH, McClure MO, Larkin DF, Lechler RI, George AJ. Expression of
indoleamine 2,3-dioxygenase (IDO) by endothelial cells: implications for the control of
alloresponses. Am J Transplant 2006;6:1320. [PubMed: 16686756]
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117. Pober JS, Bevilacqua MP, Mendrick DL, Lapierre LA, Fiers W, Gimbrone MA Jr. Two distinct
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to resist immune-mediated injury. J Immunol 2000;164:3837. [PubMed: 10725745]
100. Waxman AB, Mahboubi K, Knickelbein RG, et al. Interleukin-11 and interleukin-6 protect cultured
human endothelial cells from H2O2-induced cell death. Am J Respir Cell Mol Biol 2003;29:513.
[PubMed: 12730073]
101. Lagaaij EL, Cramer-Knijnenburg GF, van Kemenade FJ, van Es LA, Bruijn JA, van Krieken JH.
Endothelial cell chimerism after renal transplantation and vascular rejection. Lancet 2001;357:33.
[PubMed: 11197359]
102. Sieveking DP, Buckle A, Celermajer DS, Ng MK. Strikingly different angiogenic properties of
endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay.
J.Am.Coll.Cardiol 2008;51:660. [PubMed: 18261686]
103. Wijelath ES, Rahman S, Murray J, Patel Y, Savidge G, Sobel M. Fibronectin promotes VEGF-
induced CD34 cell differentiation into endothelial cells. J.Vasc.Surg 2004;39:655. [PubMed:
14981463]
104. Zemani F, Silvestre JS, Fauvel-Lafeve F, et al. Ex vivo priming of endothelial progenitor cells with
SDF-1 before transplantation could increase their proangiogenic potential.
Arterioscler.Thromb.Vasc.Biol 2008;28:644. [PubMed: 18239152]
105. Min W, Pober JS, Johnson DR. Kinetically coordinated induction of TAP1 and HLA class I by IFN-
gamma: the rapid induction of TAP1 by IFN-gamma is mediated by Stat1 alpha. J Immunol
1996;156:3174. [PubMed: 8617938]
106. Collins T, Korman AJ, Wake CT, et al. Immune interferon activates multiple class II major
histocompatibility complex genes and the associated invariant chain gene in human endothelial
cells and dermal fibroblasts. Proc Natl Acad Sci U S A 1984;81:4917. [PubMed: 6431411]
107. Pober JS, Gimbrone MA Jr, Collins T, et al. Interactions of T lymphocytes with human vascular
endothelial cells: role of endothelial cells surface antigens. Immunobiology 1984;168:483.
[PubMed: 6397428]
108. Suarez Y, Shepherd BR, Rao DA, Pober JS. Alloimmunity to human endothelial cells derived from
cord blood progenitors. J Immunol 2007;179:7488. [PubMed: 18025193]
109. Khayyamian S, Hutloff A, Buchner K, et al. ICOS-ligand, expressed on human endothelial cells,
costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells. Proc Natl Acad Sci U S A
2002;99:6198. [PubMed: 11983910]
110. Karmann K, Hughes CC, Schechner J, Fanslow WC, Pober JS. CD40 on human endothelial cells:
inducibility by cytokines and functional regulation of adhesion molecule expression. Proc Natl Acad
Sci U S A 1995;92:4342. [PubMed: 7538666]
111. Kurt-Jones EA, Fiers W, Pober JS. Membrane interleukin 1 induction on human endothelial cells
and dermal fibroblasts. J Immunol 1987;139:2317. [PubMed: 3116078]
112. May LT, Torcia G, Cozzolino F, et al. Interleukin-6 gene expression in human endothelial cells:
RNA start sites, multiple IL-6 proteins and inhibition of proliferation. Biochem Biophys Res
Commun 1989;159:991. [PubMed: 2649105]
113. Beutelspacher SC, Tan PH, McClure MO, Larkin DF, Lechler RI, George AJ. Expression of
indoleamine 2,3-dioxygenase (IDO) by endothelial cells: implications for the control of
alloresponses. Am J Transplant 2006;6:1320. [PubMed: 16686756]
114. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology.
J Immunol 2004;172:2731. [PubMed: 14978070]
115. Choi J, Enis DR, Koh KP, Shiao SL, Pober JS. T lymphocyte-endothelial cell interactions. Annu
Rev Immunol 2004;22:683. [PubMed: 15032593]
116. Gatti E, Velleca MA, Biedermann BC, et al. Large-scale culture and selective maturation of human
Langerhans cells from granulocyte colony-stimulating factor-mobilized CD34+ progenitors. J
Immunol 2000;164:3600. [PubMed: 10725716]
117. Pober JS, Bevilacqua MP, Mendrick DL, Lapierre LA, Fiers W, Gimbrone MA Jr. Two distinct
monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and
transient expression of the same antigen on the surface of cultured human vascular endothelial cells.
J Immunol 1986;136:1680. [PubMed: 3485132]
Al-Lamki et al. Page 13
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118. Pober JS, Gimbrone MA Jr, Lapierre LA, et al. Overlapping patterns of activation of human
endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol
1986;137:1893. [PubMed: 3091693]
119. Carlos T, Kovach N, Schwartz B, et al. Human monocytes bind to two cytokine-induced adhesive
ligands on cultured human endothelial cells: endothelial-leukocyte adhesion molecule-1 and
vascular cell adhesion molecule-1. Blood 1991;77:2266. [PubMed: 1709380]
120. McCarty JM, Yee EK, Deisher TA, Harlan JM, Kaushansky K. Interleukin-4 induces endothelial
vascular cell adhesion molecule-1 (VCAM-1) by an NF-kappa b-independent mechanism. FEBS
Lett 1995;372:194. [PubMed: 7556668]
121. Hattori R, Hamilton KK, Fugate RD, McEver RP, Sims PJ. Stimulated secretion of endothelial von
Willebrand factor is accompanied by rapid redistribution to the cell surface of the intracellular
granule membrane protein GMP-140. J Biol Chem 1989;264:7768. [PubMed: 2470733]
122. de Fougerolles AR, Stacker SA, Schwarting R, Springer TA. Characterization of ICAM-2 and
evidence for a third counter-receptor for LFA-1. J Exp Med 1991;174:253. [PubMed: 1676048]
123. Muller WA, Weigl SA, Deng X, Phillips DM. PECAM-1 is required for transendothelial migration
of leukocytes. J Exp Med 1993;178:449. [PubMed: 8340753]
124. Schenkel AR, Mamdouh Z, Chen X, Liebman RM, Muller WA. CD99 plays a major role in the
migration of monocytes through endothelial junctions. Nat Immunol 2002;3:143. [PubMed:
11812991]
125. Cabre F, Tost D, Suesa N, et al. Synthesis and release of platelet-activating factor and eicosanoids
in human endothelial cells induced by different agonists. Agents Actions 1993;38:212. [PubMed:
8213348]
126. Strieter RM, Kunkel SL, Showell HJ, et al. Endothelial cell gene expression of a neutrophil
chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science 1989;243:1467. [PubMed: 2648570]
127. Wen DZ, Rowland A, Derynck R. Expression and secretion of gro/MGSA by stimulated human
endothelial cells. Embo J 1989;8:1761. [PubMed: 2670560]
128. Luster AD, Unkeless JC, Ravetch JV. Gamma-interferon transcriptionally regulates an early-
response gene containing homology to platelet proteins. Nature 1985;315:672. [PubMed: 3925348]
129. Kao J, Kobashigawa J, Fishbein MC, et al. Elevated serum levels of the CXCR3 chemokine ITAC
are associated with the development of transplant coronary artery disease. Circulation
2003;107:1958. [PubMed: 12695288]
130. Koga S, Kobayashi H, Novick AC, Toma H, Fairchild RL. Alloantigen-specific CD8(+) T cells
stimulate endothelial cells to produce the T-cell chemoattractants IP-10 and Mig. Transplant Proc
2001;33:459. [PubMed: 11266909]
131. Rollins BJ, Yoshimura T, Leonard EJ, Pober JS. Cytokine-activated human endothelial cells
synthesize and secrete a monocyte chemoattractant, MCP-1/JE. Am J Pathol 1990;136:1229.
[PubMed: 2113354]
132. Rollins BJ, Pober JS. Interleukin-4 induces the synthesis and secretion of MCP-1/JE by human
endothelial cells. Am J Pathol 1991;138:1315. [PubMed: 2053591]
133. Marfaing-Koka A, Devergne O, Gorgone G, et al. Regulation of the production of the RANTES
chemokine by endothelial cells. Synergistic induction by IFN-gamma plus TNF-alpha and
inhibition by IL-4 and IL-13. J Immunol 1995;154:1870. [PubMed: 7530744]
134. Shinkai A, Yoshisue H, Koike M, et al. A novel human CC chemokine, eotaxin-3, which is expressed
in IL-4-stimulated vascular endothelial cells, exhibits potent activity toward eosinophils. J Immunol
1999;163:1602. [PubMed: 10415065]
135. Imaizumi T, Matsumiya T, Fujimoto K, et al. Interferon-gamma stimulates the expression of
CX3CL1/fractalkine in cultured human endothelial cells. Tohoku J Exp Med 2000;192:127.
[PubMed: 11211312]
136. Maier JA, Hla T, Maciag T. Cyclooxygenase is an immediate-early gene induced by interleukin-1
in human endothelial cells. J Biol Chem 1990;265:10805. [PubMed: 1694171]
137. Yoshizumi M, Perrella MA, Burnett JC Jr, Lee ME. Tumor necrosis factor downregulates an
endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res 1993;73:205. [PubMed:
7685252]
Al-Lamki et al. Page 14
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endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol
1986;137:1893. [PubMed: 3091693]
119. Carlos T, Kovach N, Schwartz B, et al. Human monocytes bind to two cytokine-induced adhesive
ligands on cultured human endothelial cells: endothelial-leukocyte adhesion molecule-1 and
vascular cell adhesion molecule-1. Blood 1991;77:2266. [PubMed: 1709380]
120. McCarty JM, Yee EK, Deisher TA, Harlan JM, Kaushansky K. Interleukin-4 induces endothelial
vascular cell adhesion molecule-1 (VCAM-1) by an NF-kappa b-independent mechanism. FEBS
Lett 1995;372:194. [PubMed: 7556668]
121. Hattori R, Hamilton KK, Fugate RD, McEver RP, Sims PJ. Stimulated secretion of endothelial von
Willebrand factor is accompanied by rapid redistribution to the cell surface of the intracellular
granule membrane protein GMP-140. J Biol Chem 1989;264:7768. [PubMed: 2470733]
122. de Fougerolles AR, Stacker SA, Schwarting R, Springer TA. Characterization of ICAM-2 and
evidence for a third counter-receptor for LFA-1. J Exp Med 1991;174:253. [PubMed: 1676048]
123. Muller WA, Weigl SA, Deng X, Phillips DM. PECAM-1 is required for transendothelial migration
of leukocytes. J Exp Med 1993;178:449. [PubMed: 8340753]
124. Schenkel AR, Mamdouh Z, Chen X, Liebman RM, Muller WA. CD99 plays a major role in the
migration of monocytes through endothelial junctions. Nat Immunol 2002;3:143. [PubMed:
11812991]
125. Cabre F, Tost D, Suesa N, et al. Synthesis and release of platelet-activating factor and eicosanoids
in human endothelial cells induced by different agonists. Agents Actions 1993;38:212. [PubMed:
8213348]
126. Strieter RM, Kunkel SL, Showell HJ, et al. Endothelial cell gene expression of a neutrophil
chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science 1989;243:1467. [PubMed: 2648570]
127. Wen DZ, Rowland A, Derynck R. Expression and secretion of gro/MGSA by stimulated human
endothelial cells. Embo J 1989;8:1761. [PubMed: 2670560]
128. Luster AD, Unkeless JC, Ravetch JV. Gamma-interferon transcriptionally regulates an early-
response gene containing homology to platelet proteins. Nature 1985;315:672. [PubMed: 3925348]
129. Kao J, Kobashigawa J, Fishbein MC, et al. Elevated serum levels of the CXCR3 chemokine ITAC
are associated with the development of transplant coronary artery disease. Circulation
2003;107:1958. [PubMed: 12695288]
130. Koga S, Kobayashi H, Novick AC, Toma H, Fairchild RL. Alloantigen-specific CD8(+) T cells
stimulate endothelial cells to produce the T-cell chemoattractants IP-10 and Mig. Transplant Proc
2001;33:459. [PubMed: 11266909]
131. Rollins BJ, Yoshimura T, Leonard EJ, Pober JS. Cytokine-activated human endothelial cells
synthesize and secrete a monocyte chemoattractant, MCP-1/JE. Am J Pathol 1990;136:1229.
[PubMed: 2113354]
132. Rollins BJ, Pober JS. Interleukin-4 induces the synthesis and secretion of MCP-1/JE by human
endothelial cells. Am J Pathol 1991;138:1315. [PubMed: 2053591]
133. Marfaing-Koka A, Devergne O, Gorgone G, et al. Regulation of the production of the RANTES
chemokine by endothelial cells. Synergistic induction by IFN-gamma plus TNF-alpha and
inhibition by IL-4 and IL-13. J Immunol 1995;154:1870. [PubMed: 7530744]
134. Shinkai A, Yoshisue H, Koike M, et al. A novel human CC chemokine, eotaxin-3, which is expressed
in IL-4-stimulated vascular endothelial cells, exhibits potent activity toward eosinophils. J Immunol
1999;163:1602. [PubMed: 10415065]
135. Imaizumi T, Matsumiya T, Fujimoto K, et al. Interferon-gamma stimulates the expression of
CX3CL1/fractalkine in cultured human endothelial cells. Tohoku J Exp Med 2000;192:127.
[PubMed: 11211312]
136. Maier JA, Hla T, Maciag T. Cyclooxygenase is an immediate-early gene induced by interleukin-1
in human endothelial cells. J Biol Chem 1990;265:10805. [PubMed: 1694171]
137. Yoshizumi M, Perrella MA, Burnett JC Jr, Lee ME. Tumor necrosis factor downregulates an
endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res 1993;73:205. [PubMed:
7685252]
Al-Lamki et al. Page 14
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Page 15
138. Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA Jr. Recombinant tumor
necrosis factor induces procoagulant activity in cultured human vascular endothelium:
characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci U S A
1986;83:4533. [PubMed: 3487091]
139. Miller DL, Yaron R, Yellin MJ. CD40L-CD40 interactions regulate endothelial cell surface tissue
factor and thrombomodulin expression. J Leukoc Biol 1998;63:373. [PubMed: 9500526]
140. Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin
gene in endothelial cells. Mol Cell Biol 1988;8:5588. [PubMed: 2854203]
Al-Lamki et al. Page 15
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necrosis factor induces procoagulant activity in cultured human vascular endothelium:
characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci U S A
1986;83:4533. [PubMed: 3487091]
139. Miller DL, Yaron R, Yellin MJ. CD40L-CD40 interactions regulate endothelial cell surface tissue
factor and thrombomodulin expression. J Leukoc Biol 1998;63:373. [PubMed: 9500526]
140. Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin
gene in endothelial cells. Mol Cell Biol 1988;8:5588. [PubMed: 2854203]
Al-Lamki et al. Page 15
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Al-Lamki et al. Page 16
Table I
Molecules Expressed by Human Endothelial Cells Relevant for Antigen Presentation
Category Molecule Comment Rels
MHC HLA-A,B,C Constitutive; increased by IFN-α,β,γ TNF (20,21)
TAP1,2 Constitutive; increased by IFN-α,β,γ TNF (105)
LMP2,7 Constitutive; increased by IFN-α,β,γ TNF (105)
HLA-DR, DP, DQ Basal and induced further by IFN-γ (106)
Invariant Chain Basal and induced further by IFN-γ (106)
Costimulators LFA-3 (CD58) Constitutive (Ig superfamily) (107)
PDL-1 Constitutive; increased by IFN-γ (Ig superfamily) (108)
PDL-2 Constitutive; increased by IFN-γ (Ig superfamily) (108)
ICOS-Ligand Constitutive; increased by TNF (Ig superfamily) (109)
4-1BB Ligand Constitutive; increased by IFN-γ (TNF superfamily) (7)
CD40 Constitutive; increased by IFN-γ and TNF (TNFR
superfamily)
(110)
Ox40-Ligand Constitutive (TNF superfamily) (7)
GITR-Ligand Induced by TNF (TNF superfamily) (108)
Cytokines IL-1α Constitutive; increased by IL-1, TNF (111)
IL-6 Induced by IL-1, TNF (112)
Other Indolamine 2,3 dioxygenase Induced by IFN αβγ (113)
Transplantation. Author manuscript; available in PMC 2009 November 27.
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Al-Lamki et al. Page 16
Table I
Molecules Expressed by Human Endothelial Cells Relevant for Antigen Presentation
Category Molecule Comment Rels
MHC HLA-A,B,C Constitutive; increased by IFN-α,β,γ TNF (20,21)
TAP1,2 Constitutive; increased by IFN-α,β,γ TNF (105)
LMP2,7 Constitutive; increased by IFN-α,β,γ TNF (105)
HLA-DR, DP, DQ Basal and induced further by IFN-γ (106)
Invariant Chain Basal and induced further by IFN-γ (106)
Costimulators LFA-3 (CD58) Constitutive (Ig superfamily) (107)
PDL-1 Constitutive; increased by IFN-γ (Ig superfamily) (108)
PDL-2 Constitutive; increased by IFN-γ (Ig superfamily) (108)
ICOS-Ligand Constitutive; increased by TNF (Ig superfamily) (109)
4-1BB Ligand Constitutive; increased by IFN-γ (TNF superfamily) (7)
CD40 Constitutive; increased by IFN-γ and TNF (TNFR
superfamily)
(110)
Ox40-Ligand Constitutive (TNF superfamily) (7)
GITR-Ligand Induced by TNF (TNF superfamily) (108)
Cytokines IL-1α Constitutive; increased by IL-1, TNF (111)
IL-6 Induced by IL-1, TNF (112)
Other Indolamine 2,3 dioxygenase Induced by IFN αβγ (113)
Transplantation. Author manuscript; available in PMC 2009 November 27.
Page 17
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Al-Lamki et al. Page 17
Table II
Some Molecular Difference between Human and Mouse Endothelial Cells Relevant for Rejection
Molecule Human Mouse Rel
Class II MHC basal and inducible absent (114)
LFA-3 constitutive absent (114)
CD80 absent constitutive and inducible (114)
P-selectin constitutive and mobilizable cytokine inducible (114)
IL-8 inducible absent (114)
Activation of CD4+ T cells central and effector memory cells regulatory cells only (29,32)
Activation of CD8+ T cells memory cells only naïve and memory cells (4,31)
Transplantation. Author manuscript; available in PMC 2009 November 27.
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Al-Lamki et al. Page 17
Table II
Some Molecular Difference between Human and Mouse Endothelial Cells Relevant for Rejection
Molecule Human Mouse Rel
Class II MHC basal and inducible absent (114)
LFA-3 constitutive absent (114)
CD80 absent constitutive and inducible (114)
P-selectin constitutive and mobilizable cytokine inducible (114)
IL-8 inducible absent (114)
Activation of CD4+ T cells central and effector memory cells regulatory cells only (29,32)
Activation of CD8+ T cells memory cells only naïve and memory cells (4,31)
Transplantation. Author manuscript; available in PMC 2009 November 27.
Page 18
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Table III
Some Comparisons of Antigen Presentation by Human Endothelial Cells (115) vs. Human Dendritic Cells (116)
Property Endothelial Cell Dendritic Cell
Phagocytosis absent (in vitro only) present (when immature)
Pinocytosis active active
MHC expression basal; regulated by cytokines regulated by maturation
Cross presentation probable yes
Costimulation LFA-3 dominant; no B7 (CD80, CD86); B7 (CD80, CD86) dominant
Adhesion selective for memory T cells Cluster with naïve T cells
Activation of T cells selective for (effector) memory T cells Preferential with naïve T cells
Transplantation. Author manuscript; available in PMC 2009 November 27.
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Al-Lamki et al. Page 18
Table III
Some Comparisons of Antigen Presentation by Human Endothelial Cells (115) vs. Human Dendritic Cells (116)
Property Endothelial Cell Dendritic Cell
Phagocytosis absent (in vitro only) present (when immature)
Pinocytosis active active
MHC expression basal; regulated by cytokines regulated by maturation
Cross presentation probable yes
Costimulation LFA-3 dominant; no B7 (CD80, CD86); B7 (CD80, CD86) dominant
Adhesion selective for memory T cells Cluster with naïve T cells
Activation of T cells selective for (effector) memory T cells Preferential with naïve T cells
Transplantation. Author manuscript; available in PMC 2009 November 27.
Page 19
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Al-Lamki et al. Page 19
Table IV
Some Molecules Expressed by Human Endothelial Cells Relevant for Inflammation/Rejection
Category Molecules Comment Rels
Leukocyte Adhesion E-selectin Induced by TNF, IL-1 (117)
ICAM-1 Constitutive; increased by TNF, IL-1
IFN-γ
(118)
VCAM-1 Induced by TNF, IL-1, IL-4, IL-13 (119,120)
P-selectin Constitutive: sequestered until
translocated
(121)
ICAM-2 Constitutive (122)
Leukocyte Transmigration PECAM-1 Constitutive (123)
CD99 Constitutive (124)
Leukocyte Activation Platelet activating factor Synthesized in response to thrombin,
histamine
(125)
IL-8, Gro-α Induced by TNF, IL-1 (126,127)
IP-10 Induced by IFN-γ (129)
ITAC Induced by IFN-γ (129)
Mig Induced by IFN-γ (130)
ENA-78 Induced by IL-1 (44)
MCP-1 Induced by TNF, IL-1, IFN-γ IL-4, IL-13 (131,132)
Rantes Induced by TNF plus IFN-γ (133)
Eotaxin 3 Induced by IL-4 (134)
Fractalkine Induced by TNF, IL-1, IFN-γ (135)
Vasoactive Cyclo-oxygenase 2 Induced by TNF, IL-1 (136)
Endothelial NOS Constitutive; decreased by TNF (137)
Procoagulant Tissue factor Induced by TNF, IL-1, CD40L (138,139)
Heparan sulfate Shed by Ab + C' (84)
Thrombomodulin Constitutive; decreased by TNF, CD40L (139,140)
Transplantation. Author manuscript; available in PMC 2009 November 27.
H
-
P
A
A
u
t
h
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r
M
a
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i
p
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N
I
H
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P
A
A
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M
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s
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r
i
p
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Al-Lamki et al. Page 19
Table IV
Some Molecules Expressed by Human Endothelial Cells Relevant for Inflammation/Rejection
Category Molecules Comment Rels
Leukocyte Adhesion E-selectin Induced by TNF, IL-1 (117)
ICAM-1 Constitutive; increased by TNF, IL-1
IFN-γ
(118)
VCAM-1 Induced by TNF, IL-1, IL-4, IL-13 (119,120)
P-selectin Constitutive: sequestered until
translocated
(121)
ICAM-2 Constitutive (122)
Leukocyte Transmigration PECAM-1 Constitutive (123)
CD99 Constitutive (124)
Leukocyte Activation Platelet activating factor Synthesized in response to thrombin,
histamine
(125)
IL-8, Gro-α Induced by TNF, IL-1 (126,127)
IP-10 Induced by IFN-γ (129)
ITAC Induced by IFN-γ (129)
Mig Induced by IFN-γ (130)
ENA-78 Induced by IL-1 (44)
MCP-1 Induced by TNF, IL-1, IFN-γ IL-4, IL-13 (131,132)
Rantes Induced by TNF plus IFN-γ (133)
Eotaxin 3 Induced by IL-4 (134)
Fractalkine Induced by TNF, IL-1, IFN-γ (135)
Vasoactive Cyclo-oxygenase 2 Induced by TNF, IL-1 (136)
Endothelial NOS Constitutive; decreased by TNF (137)
Procoagulant Tissue factor Induced by TNF, IL-1, CD40L (138,139)
Heparan sulfate Shed by Ab + C' (84)
Thrombomodulin Constitutive; decreased by TNF, CD40L (139,140)
Transplantation. Author manuscript; available in PMC 2009 November 27.
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