Chemokines are important regulators in the development, differentiation, and anatomic location of leukocytes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4 ؉ T helper 1 (Th1) cells. We sought to determine the role of CCR5 in islet allograft rejection in a streptozotocin-induced diabetic mouse model. BALB/c islet allografts transplanted into CCR5 -/-(C57BL/6) recipients survived significantly longer (mean survival time, 38 ؎ 8 days) compared with those transplanted into wild-type control mice (10 ؎ 2 days; P < 0.0001). Twenty percent of islet allografts in CCR5 -/-animals without other treatment survived >90 days. In CCR5 -/-mice, intragraft mRNA expression of interleukin-4 and -5 was increased, whereas that of interferon-␥ was decreased, corresponding to a Th2 pattern of T-cell activation in the target tissues compared with a Th1 pattern observed in controls. A similar Th2 response pattern was also observed in the periphery (splenocytes responding to donor cells) by enzymelinked immunosorbent spot assay. We conclude that CCR5 plays an important role in orchestrating the Th1 immune response leading to islet allograft rejection. Targeting this chemokine receptor, therefore, may provide a clinically useful strategy to prevent islet allograft rejection. Diabetes 51:2489 -2495, 2002 T hrough activation of the G-protein-coupled cellsurface receptor on target cells, chemokines and their receptors play a major role in the process by which leukocytes are recruited from the bloodstream into sites of inflammation, and several have been implicated in allograft rejection (1). CC chemokine receptor 5 (CCR5) is the receptor for the proinflammatory chemokines: RANTES (regulated on activation normal T-cell expressed and secreted) (CC chemokine ligand 5 [CCL5]), macrophage inflammatory protein (MIP)-1␣ (CCL3), and MIP-1␤ (CCL4) (1). Th1 cells express CCR5 and CXC chemokine receptor 3 (CXCR3) following activation, whereas activated T helper 2 (Th2) cells express CCR3, CCR4, and CCR8 (2,3). Synthesis of the chemokines MIP-1␣, MIP-1␤, and RANTES has been shown to be associated with a Th1 response (4). In vitro chemotaxis assays have shown that, whereas MIP-1␣, MIP-1␤, and RANTES were efficient chemoattractants for Th1 cells to induce a dose-dependent transmigration, Th2 cells were not attracted by these chemokines (5). In heart allografts, the early expression of some chemokines, including MIP-1␣ and MIP-1␤, subsides by day 7-9 posttransplant and is replaced by a late expression of other chemokines such as inducible protein (IP)-10 (CXCL10), monokine induced by interferon-␥ (Mig) (CXCL9) (ligands for CXCR3), and RANTES (a ligand for CCR5) (6). Met-RANTES, a CCR5 antagonist, can reduce the severity of chronic renal allograft rejection in the Lewis3 Fisher model. This effect has been attributed to blocking RANTES-induced firm adhesion of monocytes, monocyte arrest, and recruitment (7). It has recently been demonstrated that targeting CCR5 prolongs vascularized cardiac allograft survival in a mouse transplant mod...

Although it has often been assumed that transplanted allogeneic islets can be destroyed by recurrent autoimmunity in recipients with type 1 diabetes, definitive evidence is lacking and the settings in which this may occur have not been defined. To address these issues, we compared the survival of islet transplants (subject to tissue-specific autoimmunity) with cardiac transplants (not subject to tissue-specific autoimmunity) from various major histocompatibility complex (MHC)-matched and -mismatched donors transplanted into autoimmune NOD recipients. We found that when recipients were treated with combined B7 and CD154 T-cell costimulatory blockade, hearts survived best with better MHC matching, whereas islets survived worst when the donor and recipient shared MHC class II antigens. In the absence of full or MHC class II matching, there was no difference in the survival of islet and cardiac allografts. We also found that the tendency of NOD mice to resist tolerance induction by costimulation blockade is mediated by both CD4+ and CD8+ T-cells, not directly linked to the presence of autoimmunity, and conferred by non-MHC background genes. These findings have clinical importance because they suggest that under some circumstances, avoiding MHC class II sharing may provide better islet allograft survival in recipients with autoimmune diabetes, since mismatched allogeneic islets may be resistant to recurrent autoimmunity. Our results may have implications for the design of future clinical trials in islet transplantation.

Our results provide the first evidence that newly established autoimmune islet destruction in NOD mice responds to a short course of anti-CD4 mAb. In contrast, costimulation blockade is ineffective in this clinically relevant model.