Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection

By W. Hancock, B. Lu, Wei Gao, V. Csizmadia, K. Faia, J. A. King, S. Smiley, Mai Ling, N. Gerard, C. Gerard. Journal of Experimental Medicine, 2000

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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)-γ–inducible protein of 10 kD (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T cell α 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/4401b2fdb1f335872c7a2eec08aaaa110f2476f4

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Citations in the corpus

T-bet controls regulatory T cell homeostasis and function during type-1 inflammation (2009, background): “The T-bet target genes encoding CXCR3 and IL-12Rβ2 have been linked to the differentiation and selection of T H 1 cell”
Chemokine receptors: multifaceted therapeutic targets (2002, background): “In the case of the truncated CCR2 antagonist (9-68)-CCL2, the efficacy of blockade of CCR2 has been shown in the spontaneous model of arthritis in”
IFN-γ-Inducible Protein 10 (IP-10; CXCL10)-Deficient Mice Reveal a Role for IP-10 in Effector T Cell Generation and Trafficking1 (2002, background): “Furthermore, recent studies with the IP-10 / mice we describe here and with CXCR3 / mice demonstrated a role for donorderived IP-10 and host-derived CXCR3 in the recruitment of NK cells and effector T cells into murine cardiac allografts delaying rejection (41, 58).”
Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming (2004, methodology): “This work was supported by grants from the Swiss National Science Foundation (31-63885) and from the European Commission (‘Memovax’ QLK2-CT-2001-01205 and ‘Main’ FP6-502935).”
Chemokines and chemokine receptors in leukocyte trafficking. (2002, background): “CXCR3 / and CCR5 / mice or mice treated with neutralizing antibodies to either of these receptors appear to be resistant to the development of cardiac allograft rejection (55, 75).”