CCR1/CCL5(RANTES)receptor-ligandinteractionsmodulateallogeneicT-cell responsesandgraft-versus-hostdiseasefollowingstem-celltransplantation

Acute graft-versus-host disease (GVHD) and leukemic relapse are serious complications of allogeneic stem-cell transplantation (SCT). Recruitment of activated T cells to host target tissues or sites of leukemic infiltration (graft-versusleukemia [GVL]) is likely mediated by chemokine receptor‐ligand interactions. We examined the contribution of donor cellCCR1expressiontothedevelopmentof GVHD and GVL using a well-established murine SCT model (B6 3 B6D2F1) and CCR1-deficient mice (CCR1! /! ). Allo-SCT with CCR1! /! donor cells significantly reduced systemic and target organ GVHD severity, and CCR1 expression on both T cells and accessory cells contributed to GVHDmortality.SignificantGVLactivitywas preserved following CCR1! /! SCT, but the survivaladvantagediminishedwithincreasing tumor burden. We then explored the effects of CCR1 expression on allo-specific T-cellresponses.Althoughcytolyticeffector functionwasmaintainedonaper-cellbasis, T-cell proliferation and IFN" secretion were significantly reduced both in vivo and in vitro.T-cellfunctionwaspartiallydependent on interactions between CCR1 and CCL5. Collectively, these data demonstrate that CCR1 expression on donor cells contributes to the development of both GVHD and GVL,andsuggestthatCCR1/CCL5receptorligand interactions modulate allo-specific T-cell responses occurring in this context. (Blood.2007;110:3447-3455)