The Role of CC Chemokine Receptor 5 (CCR5) in Islet Allograft Rejection

Abstract

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...

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

“…We conclude that direct blockage of CCL3 and CCL5 or the antagonism of CCR5 by maraviroc currently applied for HIV patients may provide a new therapeutic target to ameliorate disease progression in type 1 diabetes as has been shown in animal models [4,5].…”

“…These data suggest that chemotaxis via ligands of CCR5 controls the invasive as well as the destructive potential of islet infiltrating T-cells. Similarly, in a murine islet transplantation model, BALB/c islet allograft transplanted into CCR5−/− C57BL/6 recipients survived significantly longer compared to the CCR5+/+ wildtype C57BL/6 recipients [5]. Interestingly to note, β-cells do also secrete CCL3, CCL4 and CCL5 in case of stress or cell death (apoptosis) in addition to the secretion of these chemokines by infiltrating T-cells [4,[6][7][8].…”

Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non‐obese diabetic mice

“…Thus, NOD mice congenic for the Idd9 genetic interval have been generated; these animals develop insulitis, but not diabetes [22]. The role of CCR5 in islet protection has indeed been established, as islet allografts survive significantly longer in CCR5 -/-mice [23]. Our data showing inhibition of diabetes but not of insulitis after anti-CCR5 treatment of NOD mice suggest that chemotaxis controls the invasive and destructive potential of islet-infiltrating of CCR5 + lymphocytes.…”

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

“…These observations reveal a novel phenotype in Ccr5 À/À mice favoring alternative activation of macrophages. This finding may account for the improved transplant survival described in Ccr5-deficient mice [12][13][14][15], in primates treated with CCR5 antagonists [33] and in humans homozygous for the CCR5D32 allele [8]. Furthermore, this observation may prove to be of considerable significance for the progression of chronic inflammatory and fibrosing disease processes.…”

“…Phenotypic alterations in these mice have been analyzed in different transplant models including experimental cardiac, carotid artery, islet, and renal allografts [12][13][14][15][16][17][18]. Kidney transplantation represents the most frequent organ replacement therapy in humans, but despite major advances in the treatment of acute rejection, long-term graft survival has not markedly improved.…”