Beneficial Effects of Targeting CCR5 in Allograft Recipients. Transplantation 2001; 72: 1199.

Abstract

CHEMOKINES AND ALLOGRAFT REJECTION: NARROWING THE LIST OF SUSPECTS Chemokines have been implicated as mediators of allograft rejection by virtue of their diverse roles as regulators of leukocyte adhesion, migration, and activation of effector function (1). The receptors for chemokines, a subfamily of G protein-coupled receptors with seven transmembrane domains, are differentially expressed on leukocytes and various other cell types and, in combination with their ligands, are key regulators of leukocyte biology (2). The regulation of immune effector cell infiltration into an allograft is a complex process (Fig. 1) (1,2). Until recently, it has been difficult to dissect the relative role of each chemokine in the inflammatory processes leading to allograft rejection, especially because many chemokines and chemokine receptors are seemingly redundant. Studies using targeted disruption of specific chemokine receptors, receptor antagonists, and blocking antireceptor antisera, have now begun to shed light on the pathophysiological roles of specific receptors in allograft rejection (Table 1). Figure 1: Chemokine gradients facilitate recruitment of inflammatory cells from peripheral circulation into sites of inflammation. This multistep process is central to the generation of inflammatory infiltrate during organ transplant rejection. Chemokine expression within tissue may also act to modulate immune effector cell function (reviewed in Ref. 1).Table 1: Recent developments in chemokine receptor blockade and allograft rejectionAllograft rejection is mediated to a significant degree by the influx of monocyte and T effector cells (Fig. 1) (1). The induction of chemokines by “stressed” tissues during allograft rejection is accompanied by the infiltration of leukocytes bearing the respective chemokine receptors (1). The chemokine receptors expressed by different T cell populations have been linked to Th1/Th2-like effector responses of receptor expressing cells. Allograft rejection is thought to be primarily the result of a Th1-type immune response. Th1-like cells often express CXCR3 and CCR5, while Th2 cells can express CCR3, CCR4, and CCR8 (2). In this issue of Transplantation, Gao et al. show that CCR5 plays a key role in cardiac allograft rejection in a mouse model. These results, together with a recent report by Fischereder and Luckow et al. (3), suggest that targeting this chemokine receptor may be useful clinically. CCR5 expression is induced after the activation of monocytes and T cells and an increase of CCR5+ infiltrating leukocytes is seen during both acute and chronic phases of renal allograft rejection (1). During renal transplant rejection, the distribution of CCR5 positive leukocytes in areas of endothelialitis, tubulitis, and interstitial infiltrates mirrors the general expression of chemokines such as RANTES and MIP-1α(1). Although mice deficient in chemokines, such as MIP-1α or RANTES, reject experimental cardiac allografts normally, mice treated with neutralizing anti-CCR5 antibodies show prolonged allograft survival. CCR5 knock-out animals disparate in MHC class II accept grafts permanently. Finally, treatment with low dose cyclosporin A augments the effects of CCR5 blockade. The functional importance of CCR5+ leukocytes in human renal allograft survival has been demonstrated in a study of patients genetically lacking CCR5 (3). Approximately 1% of northern Europeans are homozygous for a null allele of CCR5 (CCR5Δ32). Due to a 32-base pair deletion within the coding region of the gene, these individuals lack functional receptor. As CCR5 represents the major coreceptor for M-tropic strains of HIV-1, individuals homozygous for CCR5Δ32 are highly resistant to productive HIV infection. CCR5Δ32 homozygotes appear healthy, and apart from their resistance against HIV-1 infection, they show no obvious phenotype. The prevalence of the CCR5Δ32 genotype was studied in a large cohort of renal transplant recipients. The absence of CCR5 (homozygous CCR5Δ32) correlated significantly with long-term engraftment as compared to the heterozygous or wild-type allele, suggesting an important role for CCR5 in development of chronic renal allograft dysfunction (3). The receptors CCR1 and CCR5 are differentially expressed on leukocyte subsets (2). Human blood monocytes express high levels of CCR1 and low levels of CCR5. By contrast, CD45RO+ “memory” T cells in general express lower levels of CCR1 and high levels of CCR5 (3). The redundancy of receptors for one chemokine implies a specialized role in leukocyte emigration. Weber et al. studied the functional contributions of CCR1 and CCR5 in recruitment of human blood monocytes and Th1-like/CD45RO+ T cells mediated by RANTES/CCL5 bound to inflamed microvascular endothelium under flow (4). Using selective CCR1 and CCR5 receptor antagonists, they found that, regardless of the relative level of receptor expression, RANTES-induced arrest of these cells was mediated predominantly by CCR1. Nevertheless, both CCR1 and CCR5 could support transendothelial chemotaxis towards RANTES/CCL5. This suggests specialized involvement of apparently redundant receptors in distinct steps of leukocyte trafficking. CCR1 was the first CC chemokine receptor to be identified (2). CCR1 is expressed by subpopulations of CD3+, CD4+, CD8+, and CD16+ leukocytes in the peripheral blood and binds MIP-1, RANTES, MCP-2, MCP-3, and other chemokine ligands. In addition, mesangial cells, after stimulation by proinflammatory cytokines, express CCR1 (1). In transplantation studies, mice lacking CCR1(-/-) show prolongation of cardiac allograft survival. Class II-mismatched allografts can be permanently accepted by CCR1(-/-) recipients and cardiac allografts transplanted across class I- and class II- were rejected more slowly than controls. Subtherapeutic doses of cyclosporin A enabled permanent allograft acceptance in CCR1(-/-) recipients with no sign of chronic rejection (5). In rat heterotopic heart transplant models, efficacy for CCR1 receptor blockade using a small molecule antagonist was demonstrated (6). Analogous to the results obtained with CCR1(-/-) mice, treatment of rats with BX 471 and a sub-therapeutic dose of cyclosporin A was effective in prolonging cardiac allograft survival (6). Some of the most compelling data on chemokine/chemokine receptor interaction and transplantation come from studies of the roles of IP-10/CXCL10 and CXCR3 in allografts (7,8). These data emphasized the pivotal role of donor-derived IP-10 and host CXCR3 expressing T cells in initiating alloresponses. T cells up-regulate expression of CXCR3 after activation. In addition, B cells, NK cells, and mesangial cells can also express CXCR3 (1). During acute cardiac allograft rejection in human and mouse, IP-10/CXCL10, Mig/CXCL9, and I-TAC/CXCL11, all ligands for CXCR3, are induced (7,8). Blocking CXCR3 with anti-CXCR3 monoclonal antibody prolongs cardiac allograft survival in mice. Mice deficient for CXCR3(-/-) are highly resistant to acute allograft rejection and, when treated with a transient, subtherapeutic dose of cyclosporin A, maintain their allografts permanently, without evidence of chronic rejection (8). These data suggest a pivotal role for CXCR3/CXCL10 in cardiac allograft rejection and suggest a rationale for the use of agents that block CXCR3 in the treatment of allograft rejection. These recent developments have improved our understanding the role of specific chemokine receptors in the pathophysiology of allograft dysfunction. The data are very encouraging regarding the potential for future therapies directed at CCR5, CCR1, and/or CXCR3 blockade. Clearly, antagonists for chemokines and their receptors may become important therapeutics in treatment of acute and chronic allograft rejection.