Differential Expression of Chemokines and Chemokine Receptors in Murine Islet Allografts

Abstract

Abstract. Chemokines and their receptors play a pivotal role in the initiation and amplification of the immune response. Investigated was their differential expression after syngeneic and allogeneic islet transplantation. During the 7 d after transplantation, the chemokines MCP-1, MCP-2, RANTES, MIG, IP-10, I-TAC, and two CC chemokine receptors CCR2 and CCR5 were highly expressed in allografts when compared with isografts. Disrupting the CCR2 and CCR5 pathways individually resulted in prolongation of the survival time 16.1 Ϯ 0.4 and 15.8 Ϯ 0.9 d, respectively, of fully major histocompatibility complex-mismatched islet grafts compared with wildtype controls (11.2 Ϯ 1.0 d). Blockade of both receptors had no synergistic effect. Rapamycin-treated wild-type recipients rejected their grafts at 17.4 Ϯ 2.2 d, in contrast to rapamycintreated CCR2Ϫ/Ϫ recipients at 38 Ϯ 8.6 d (P ϭ 0.025). The disruption of the CCR2 and CCR5 signaling, alone or in combination, moderately prolong islet allograft survival. However, the combination of low-dose immunosuppression and targeting of CCR2 greatly augmented islet graft survival.Leukocyte infiltration of pancreatic islets is the characteristic feature in acute rejection after islet transplantation. In addition to adhesion molecules, such as selectins and integrins, the complex process of extravasation and influx of leukocytes subsets into the site of tissue injury is mediated to a significant extent by the expression of specific chemokines and chemokine receptors. The chemokine superfamily is separated into four general branches (CL, CCL, CXCL, and CX3CL chemokines) on the basis of cysteine residues within their primary amino acid sequence. The biologic actions of chemokines are mediated through their interaction with a large family of G protein-coupled receptors (i.e., C, CC, CXC, and CX3C receptors) (1). During the development of allograft rejection of vascularized organs, a variety of genes of the chemokine system are prominently expressed (2,3). Targeting chemokine receptors, including CCR1, CCR5, CXCR3, and CX3CR1, with either knockout animals or monoclonal antibodies has resulted in delayed rejection of vascularized heterotopic cardiac transplants (3,4). Recently, the role of CCR2, CCR5, and CXCR3 has also been demonstrated in an islet transplantation model, with conflicting results (5,19,20). To date, little is known of the effect of CCR2 blockade in allograft rejection in combination with low-dose immunosuppression and the simultaneous blockage of CCR2 and CCR5. We investigated the differential chemokine and chemokine receptor expression in syngeneic and allogeneic islet grafts. On the basis of the initial screening, we investigated the importance of the CCR2 and CCR5 pathways in mediating islet allograft rejection. Materials and Methods Mice and the Diabetic ModelAnimals were treated in strict compliance with regulations established by the Institutional Animal Care and Use Committee. Mice were born and housed under specific-pathogen-free conditions. The recipients were render...

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.…”

“…Initially, cardiac [12,13], islet [14,15] and carotid artery [12] transplantation models were performed. In these experiments, Ccr5 deficiency of the recipient had a beneficial effect on the transplant and led to modest prolongation of graft survival.…”

“…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.…”

Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival

“…In addition to CXCR5, regulatory clones also showed overexpression of other genes associated with chemotaxis, including the chemokine receptors CCR2 and CCR3. The ligands of CCR2 and CCR3, such as MCP-1, MCP-2, and MCP-3, Eotaxin, and RANTES, have been detected in transplanted allografts in both humans and animal models (51)(52)(53)(54). This suggests that DN Treg cells could home in to the transplanted graft through CCR2 and/or CCR3, possibly in conjunction with CXCR5.…”

The Role for Monocyte Chemoattractant Protein-1 in the Generation and Function of Memory CD8+ T Cells

“…In contrast, chemokines and chemokine receptors mediate leukocyte recruitment and the rejection of allografts (38 -42). Blocking the MCP-1/CCR2 chemokine pathway prolongs allograft survival (43)(44)(45)(46). However, it is unclear whether MCP-1 is required for allograft rejection mediated by memory T cells.…”