Anti-CD3 preconditioning separates GVL from GVHD via modulating host dendritic cell and donor T-cell migration in recipients conditioned with TBI

Abstract

Host dendritic cells (DCs) play a critical role in initiating graft-versus-host dis- ease (GVHD) and graft-versus-leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treat- ment of hematologic malignancies by al- logeneic hematopoietic cell transplanta- tion (HCT). Here, we show that preconditioning with anti-CD3 monoclo- nal antibody before conditioning with to- tal body irradiation (TBI) prevents GVHD but retains GVL in a HCT model of major histocompatibility complex (MHC)-mis- matched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T-cell expression of homing and chemokine receptors, and inhibition of GVHD target tissue expres- sion of chemokines. Furthermore, inhibi- tion of donor T-cell expression of gut homing a4(β7 and chemokine receptor (CCR)9 by anti-CD3 preconditioning re- sults from a reduction of CD103+ DCs in draining mesenteric lymph nodes (LNs), which is associated with down-regulation of DC expression of CCR7, a receptor required for tissue DC migration to drain- ing LNs. These results indicate that anti-CD3 preconditioning reduces not only tissue release of chemokines but also prevents tissue DC migration to draining LNs and subsequently reduces the capac- ity of DCs of draining LNs to imprint donor T-cell tissue tropism. Therefore, modulation of host DCs by anti-CD3 pre- conditioning before HCT represents a new approach for separating GVL from GVHD. © 2009 by The American Society of Hematology.