Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection

Abstract

IntroductionMononuclear cell recruitment to an allograft is a classic hallmark of cellular rejection. At least in broad terms, such leukocyte recruitment from the vascular pool across activated endothelial cells and into tissues is now reasonably well understood (1). Thus, leukocytes roll along selectin-expressing endothelium adjacent to a chemoattractant source, attach more firmly, change shape, migrate between adjacent endothelial cells as a result of integrin and other adhesion molecule binding, and migrate through extravascular tissues along chemotactic gradients to reach their destination. The latter chemokine/chemokine receptor phase is the least understood, with little in vivo data available. However, given the burgeoning field of chemokine biology, dissecting which molecules are generated in a given inflammatory setting, and especially the nature of chemokine receptors responsible for leukocyte recruitment, might well prove key to developing better therapeutic strategies for the prevention and treatment of allograft rejection. The current literature on chemokine receptor expression in organ transplants is limited to 2 papers noting expression of CXCR4 (ref. The current studies involve serial analysis of intragraft chemokine and chemokine receptor expression within completely MHC-mismatched mouse cardiac allografts. On the basis of our initial data, in which several chemokine receptors and their ligands were associated with host mononuclear cell infiltration, we undertook a detailed analysis of the significance of 1 of the more highly expressed chemokine receptors, CCR1 (4), which binds RANTES, macrophage inflammatory protein 1-alpha (MIP-1α), and various monocyte chemoattractant proteins (MCPs). Our studies demonstrate that compared with control CCR1 +/+ mice, CCR1 -/-mice show significantly delayed, or in some cases an absence of, acute or chronic rejection, such that targeting of CCR1 may eventually prove of therapeutic significance clinically. Although mononuclear cell infiltration is a hallmark of cellular rejection of a vascularized allograft, efforts to inhibit rejection by blocking leukocyte-endothelial cell adhesion have proved largely unsuccessful, perhaps in part because of persistent generation of chemokines within rejecting grafts. We now provide, to our knowledge, the first evidence that in vivo blockade of specific chemokine receptors is of therapeutic significance in organ transplantation. Inbred mice with a targeted deletion of the chemokine receptor CCR1 showed significant prolongation of allograft survival in 4 models. First, cardiac allografts across a class II mismatch were rejected by CCR1 +/+ recipients but were accepted permanently by CCR1 -/-recipients. Second, CCR1 -/-mice rejected completely class I-and class II-mismatched BALB/c cardiac allografts more slowly than control mice. Third, levels of cyclosporin A that had marginal effects in CCR1 +/+ mice resulted in permanent allograft acceptance in CCR1 -/-recipients. These latter allografts showed no sign of chronic rejection 50-...

Differential Chemokine and Chemokine Receptor Gene Induction by Ischemia, Alloantigen, and Gene Transfer in Cardiac Grafts

“…These results support previous reports of the presence of these molecules in rejecting grafts, and prolonged graft survival in corresponding knockout or antibody-treated recipients (25)(26)(27)(28). In contrast to the induction of inflammatory chemokines on day 7, CCR7 and its ligand CCL21 were induced as early as day 3, remained at high levels on day 7, but decreased to baseline by day 14.…”

Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours

“…A recent study of acute and chronic graft rejection models is of interest. Graft survival in mice with a targeted gene disruption of CCR1 was significantly prolonged and permanent engraftment occurred in some of these mice (Gao et al, 2000). We propose that the CCR1 receptor may also be a therapeutic target in human epithelial ovarian cancer.…”

The chemokine receptor CCR7 controls lymph node‐dependent cytotoxic T cell priming in alloimmune responses

“…anti-IP-10/CXCL10 mAb (14 days allograft survival), anti-MIG/CXCL9 mAb (19 days), anti-CCR5 mAb (18 days) or CCR1 -/-deficiency (13.5 days) [10][11][12][13]. In CCR5 -/-and CXCR3 -/-mice, transplant rejection was delayed until 22 days [12] and 58 days post transplantation [13], respectively.…”

“…In this light, a cardiac allotransplantation model showed that the chemokine receptors CCR1 and CCR5, as expressed on macrophages and T cells, and CXCR3, as expressed predominantly on activated T cells, are of functional significance for CD4 + T cell activation and cardiac allograft rejection [11][12][13]. Although it is generally accepted that homeostatic chemokines and their receptors are necessary for the coordinated homing of APC and lymphocytes to secondary lymphoid organs and subsequently for the activation of an acquired immune response [5,7,8], little information is available on the role of homeostatic chemokines/chemokine receptors in alloantigen-dependent graft rejection.…”