CXCR3 Antagonism Impairs the Development of Donor-Reactive, IFN-[gamma]-Produclng Effectors and Prolongs Allograft Survival

• Published in: Transplantation Vol. 87; no. 3; pp. 360 - 369
• Main Authors: Rosenblum, J M, Zhang, Q-W, Siu, G, Collins, T L, Sullivan, T, Dairaghi, D J, Medina, J C, Fairchild, R L
• Format: Journal Article
• Language: English
• Published: 15-02-2009
• ISSN: 0041-1337

Background. Current immunosuppression regimens are toxic to transplant recipients and, in many cases, acute rejection episodes occur because of escape of donor-reactive lymphocytes from the immunosuppression. T cells are the mediators of acute, cell-mediated graft damage and are hypothesized to use the CXCR3 chemokine axis for migration into the allograft. This study investigates the effect of CXCR3 blockade using a nonpeptide, small molecule inhibitor, AMG1237845, in murine cardiac allograft survival. Methods. C57BL/6 (H-2b) mice received vascularized cardiac allografts from A/J (H-2a) donors and were treated with the CXCR3 antagonist. Hstologic and flow cytometric analyses were used to measure infiltration of leukocytes, and quantitative reverse-transcriptase polymerase chain reaction and interferon-[gamma] ELISPOT assays were used to measure donor-specific reactivity. Results. CXCR3 antagonism modestly prolonged allograft survival compared with vehicle treatment, but at time-matched intervals posttransplant, neutrophil, CD8+, and CD4+ T cell infiltration was indistinguishable. Although proliferation of donor-reactive naive T cells was unaffected by CXCR3 antagonism, the frequency of interferon-[gamma]-producing cells in the recipient spleen was significantly reduced by AMG1237845 treatment. CXCR3 blockade for 30 days synergized with short-term, low-dose anti-CD154 monoclonal antibodies to prolong survival past 50 days in 75% of grafts and past 80 days in 25% of the cases. Conclusions. These results indicate that in synergy with co-stimulation blockade, CXCR3 is a viable therapeutic target to prevent acute graft rejection.