Requirement of the chemokine receptor CXCR3 for acute allograft rejection.
Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein-coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-gamma-inducible protein of 10 kD (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T cell alpha chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3(-/)-) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3(-/)- allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR(+/+) mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.
Hancock
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Millennium Pharmaceuticals, Incorporated, Cambridge, Massachusetts 02139, USA. whanock@mpi.com
Lu
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Gao
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Csizmadia
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Faia
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King
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Smiley
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Ling
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Gerard
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Gerard
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D000208:Acute Disease; D000818:Animals; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016296:Mutagenesis; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
C515187:CXCR3 protein, human; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine