Cytotherapy (2001) Vol. 3, No. 3, 211–220
211© 2001 ISHAGE
Immune reconstitution following hematopoieticstem-cell transplantationN Novitzky and GM Davison The University of Cape Town Leukaemia Centre and the Department of Haematology, Groote Schuur Hospital, Cape Town, South Africa
Correspondence to: Nicholas Novitzky, Department of Haematology, University of Cape Town, Medical School, Anzio Road,Observatory, 7925, Cape, South Africa.
BackgroundReconstitution of the immune system following allogeneic stem-celltransplantation is a complex process that requires successful engraft-ment of the hematopoietic stem cell, as well as adequate thymic function.As the majority of patients have reduced thymic function due to age,hormonal changes, as well as the damage caused by conditioning andGvHD, immune recovery is often delayed and incomplete. Followinggraft infusion there is rapid proliferation of natural killer (NK) cellsthat appear to proceed directly from the hematopoietic stem cell. B-cellfunction is dependent on specific maturation development in the BMmicro-environment, as well as CD4 help. The CD8 population expandsrapidly due to proliferation of many memory cells that react againstClass I Ags, as well as viral molecules. Expansion of T-helper cells orig-inates mainly from the memory pool that is present in the bone marrowgraft. Naive cells require competent thymus hence the CD4 cell counts
may be subnormal with clinical immunodeficiency. Controversyremains as to the capacity of the thymus to recover and thus extrathymic proliferation of T cells have been postulated. However these cellsappear to have a limited capacity to expand and a fixed repertoire.
DiscussionDonor lymphocyte infusions may contribute a competent CD4 popula-tion that can cause GvHD, but have limitations in the capacity torespond to new antigens. Future research needs to be concentrated onimproving the capacity of the thymus to reconstitute a functional naivepopulation.
Keywordsimmunosuppression, T-cell depletion, opportunistic infections.
IntroductionFor transplantation of stem cells to be successful, a com-plete reconstitution of both the hematopoietic and immunesystems needs to take place. While there is considerableunderstanding regarding the mechanisms of hematopoieticrecovery, information on lymphoid recuperation aftertransplantation is less comprehensive. In mammals, lym-phopoiesis is initiated in the BM, but for an effectiveimmune system to develop, complex interactions betweenthe lymphoid progeny and diverse cell populations in thethymus and the lymph nodes, or other sites of Ag presen-tation need to occur. In the transplantation set-up, further complexities areadded due to variable degrees of MHC incompatibilitiesbetween donor and recipient. In this context, measures that
prevent graft rejection and recurrence of the malignancy,or promote the effective down-modulation of GvHD, allhave an effect on immune recovery post-transplantation,clouding our understanding further [1–3]. Animal transplantation studies showed that, in normaladult mice, lymphoid regeneration occurred mainly fromhematopoietic stem cells. Following their release from theBM, T-cell progenitors home into the thymus: athymicmice radiation chimeras given T-cell depleted BM haveremained T-cell deficient [4]. The presumption that simi-lar pathways occur in humans has led to a number ofinferences regarding transplantation:n Stem cells can induce complete lympho-hematopoieticreconstitution.

n The thymus is central for the induction of tolerance.Therefore, thymic damage may lead to autoimmunityand, for example, chronic GvHD. n Infusion of MHC-incompatible stem cells results inimmunodeficiency.To provide a clearer perspective on immune integritypost-transplantation, differences between postnataldevelopment and recovery following stem-cell grafting, itis appropriate to review the current understanding ofboth processes. Development of T cells in the thymusImmediately after birth, T lymphocyte production in thethymus increases significantly until puberty. This organthen begins to shrink and atrophy continues throughoutlife [5]. Thus, in early childhood, the number of T-helpercells (CD4+) reaches adult levels [6,7]. In neonates, themajority of circulating T cells display a naive phenotype(CD45RA+) and lack diversity [6,8]. Compared withmature cells, these neonatal T lymphocytes producedecreased levels of IL-2 and IL-6, and are less efficient inproviding help to B cells. However, the immune reper-toire of mature T cells is largely determined early in lifein the thymus. The effective recognition of self-peptides on thymicepithelial cells and macrophages leads to detection andelimination of autoreactive clones (negative selection),favoring the proliferation of cells capable of interactingwith foreign Ags (positive selection), while those that areincapable of binding to self MHC-Ags die of attrition (noselection) [9]. The rearrangement of the T-cell receptor(TCR) genes occurs in the thymus during T-cell matura-tion and is a prerequisite for the generation of functionalT cells. The CD3 molecule comprises at least five invari-ant polypeptides, called c , ä , å , and è . Theimmunoglobulin-like extracellular domains of the TCR( a b or c ä ) and CD3 ( c ä and e ) polypeptides on the cellmembranes form a close association. The two types ofreceptor-containing cells are quite different in theiranatomic location. The TCR a b is present in > 95% ofperipheral T cells. In contrast, the c ä receptor-bearingcells are present in the thymus, the epidermis (in mice)and epithelia of the gastrointestinal tract (GIT), uterusand tongue [10]. Upon encounter with Ag on MHC of Ag-presentingcells (APC), thymic emigrants develop the mature(CD45RO) phenotype and acquire CD44+ [11,12]. In the
peripheral blood, T cells expressing dual positiveCD4+/CD8+ markers map to the cortical stage of thymicdevelopment of circulating immature T cells [13]. Thesepre-emigrant thymocytes are long-lived cells and have anextensive ability to proliferate in an Ag-independentmanner [14]. In humans, mature naive cells that emerge from thethymus have a well-characterized phenotype of CD3+,CD45RA+, CD45RO2, CD12, CD27+ and expressCD44dim with concomitant expression of CD4 or CD8.The mechanism governing thymocyte emigrationremains unclear, but peripheral lymphocytes appear toexert some control over thymic export [15].In the mouse model, studies looking at the develop-ment of thymocytes by repopulation of thymic lobes withT-cell precursors from foetal or adult origin, showed thatthe progenitor source determines whether the immunesystem is adult or fetal-like [16]. Berzins and colleaguestransplanted two, six and nine thymic lobes into young orold mice, and studied the thymic emigrant fraction afterrecovery and following removal of the thymic grafts.Transplantation of thymic tissue led to a respectiveincrease by 15, 50 and 77% in the T-cell pool. The T-cellnumber then stabilized at a new level of thymic export, sothat the CD4:CD8 ratio was reduced from 30.5:1 to 1.6:1.The dominant population was of an emigrant phenotype,but after removal of the transplanted thymic grafts thesevalues reversed to pre-transplant values. Berzins et al.speculated that a constant number of niches in the thy-mus control T-cell numbers and enhanced thymic exportled to expansion of the T-cell pool. As reduction ofCD4:8 ratios were not due to apoptosis of CD4 popula-tion, migration of T cells to peripheral tissues could notbe excluded [11]. Thymic function declines with time, particularly afterthe age of 15, but is probably maintained to some degreeuntil old age. Thymic cortical atrophy follows corticos-teroid release and may be promoted by pregnancy, stress,etc. Clinical studies indicate that following the reversal ofan immunodepleting condition (antiretroviral therapy inHIV+ patients; following MAb therapy; etc.), the adultorgan may be capable of contributing new T cells to thepool [17,18]. Expansion of the naive phenotype is essen-tial for restoration of the T-cell repertoire and dependson the integrity of the thymus [12]. This was confirmedby the fact that thymic function failed to recover in arecipient who had been thymectomized [19]. However,
212 N Novitzky and GM Davison