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THE ROLE OF CC CHEMOKINE RECEPTOR 5 (CCR5) AND RANTES/CCL5 IN SKIN ALLOGRAFT REJECTION.
Eun-Jee Oh, M.D. Ph.D., Hiroyuki Amano, M.D. and Robert L. Fairchild, Ph.D.. Seoul Korea, Catholic University of Korea, 137-040, Clinical Pathology and Cleveland OH, USA, Cleveland Clinic Foundation, 44106, Immunology.
The chemokine receptor CCR5 is a receptor for MIP-1alpha, MIP-1beta and RANTES. These molecules are expressed by infiltrating mononuclear cells during the rejection of clinical and experimental organ allografts, although, the role of these molecules in the pathogenesis of allograft rejection is poorly understood. To determine the role of CCR5 in skin allograft rejection, we studied intragraft events during rejection of full thickness trunk skin grafts from MHC full mismatched A/J (H-2k) donors on C57BL/6 (H-2b) wild-type CCR5+/+ or CCR5-/- recipients. A/J skin allografts transplanted to CCR5-/- recipients survived significantly longer (mean survival time, 17 ± 2 days) compared with wild-type recipients (12 ± 1 days; P < 0.024), and had marked reduction in T cell infiltration at day 12 post-transplant. T cells from lymph nodes draining the allograft did not express CCR5 until day 11 posttransplant. ELISPOT assays indicated equivalent numbers of primed IFN-g producing, alloreactive T cells at day 7 post-transplant but at day 12 post-transplant the number increased in wild-type recipients but remained steady in CCR5-/- recipients. Alloreactive T cell proliferation using in vitro MLR assays demonstrated that T cells from CCR5-/- allograft recipients have decreased proliferative response. Injection of RANTES AS into C57BL/6 recipients A/J skin transplanted induced prolonged graft survival and decreased priming. These findings suggest that CCR5 and its ligand, RANTES play an important role in extending alloreactive T cell proliferation beyond the initial priming. Targeting this chemokine receptor may provide a clinically useful strategy to inhibit T cell activation and prevent allograft rejection.