Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection

Abstract

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.

Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy

“…23,24 To examine the role of this group of angiostatic chemokines, which are selective ligands for 25 the ability of IL-12 plasmid DNA gene transfer to inhibit angiogenesis was tested in CXCR3 À/À knockout mice. 26 The same naked DNA administration of the IL-12 plasmid again gave statistically significant inhibition of angiogenesis in these mice in vivo ( Figure 3c), demonstrating that these angiostatic chemokines are not the major mechanism mediating angiogenesis inhibition in this system.…”

“…Host animals utilized were male mice from either C57BL/6N immunocompetent, 6-week athymic (nu/nu, CD1 obtained from Charles River, Calco, LC, Italy), 8-to 10-week-old male IFN-g À/À mice on the BALB-c H2 d background (Jackson Laboratory, Barr Harbor, ME, USA) or CXCR3 knockout mice on the C57BL/6N background 26 kindly supplied by Prof. Craig Gerard, Harvard, MA, USA. All the animals were housed under specific pathogen-free conditions according to current European Community guidelines.…”

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

“…We have previously shown that intragraft expression of key chemoattractant pathways, especially involving CXCR3 and CCR5 in the case of fully MHC-disparate allografts, is markedly blunted by CD154/DST costimulation blockade [17][18][19], as is intragraft expression of PD-1 and PD-L1 [12]. We now report that, compared to WT mice, use of costimulation blockade in PD-1 -/-recipients had markedly reduced efficacy, resulting in significantly increased intragraft mRNA levels of IL-2 and IFN-c cytokines, as well as components of the IP-10/CXCR3 and RANTES/CCR5 chemokine/chemokine receptor pathways (Fig.…”

Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3‐signaling chemokines

“…C57BL/6, TCRˇ-/- [60] and CXCR3 -/- [61] mice were bred at the animal facilities of the Max-Planck-Institute for Infection Biology at the Bundesamt für Risikobewertung (BfR) in Berlin under specific pathogen-free (SPF) conditions. Sex-and age-matched mice were used for all experiments under conventional housing conditions.…”