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Transplantation. 2009 Feb 15;87(3):360-9. doi: 10.1097/TP.0b013e31819574e9.

CXCR3 antagonism impairs the development of donor-reactive, IFN-gamma-producing effectors and prolongs allograft survival.

Author information

1
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. jmr55@case.edu

Abstract

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-2) mice received vascularized cardiac allografts from A/J (H-2) donors and were treated with the CXCR3 antagonist. Histologic 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 naïve 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.

PMID:
19202440
PMCID:
PMC2738925
DOI:
10.1097/TP.0b013e31819574e9
[Indexed for MEDLINE]
Free PMC Article

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