CXCR3 Antagonism Impairs the Development of Donor-Reactive, IFN-γ-Producing Effectors and Prolongs Allograft Survival
| Autor: | Daniel J. Dairaghi, Qiwei Zhang, Joshua M. Rosenblum, Tassie L. Collins, Robert L. Fairchild, Julio C. Medina, Timothy J. Sullivan, Gerald Siu |
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| Rok vydání: | 2009 |
| Předmět: |
Graft Rejection
Chemokine Receptors CXCR3 Transplantation Heterotopic Mice Inbred A medicine.medical_treatment chemical and pharmacologic phenomena CXCR3 Article Interferon-gamma Mice Chemokine receptor medicine Animals Transplantation Homologous Interferon gamma Heart transplantation Mice Inbred BALB C Transplantation biology Effector Graft Survival Immunosuppression Blockade Mice Inbred C57BL surgical procedures operative Immunology biology.protein Heart Transplantation Immunosuppressive Agents medicine.drug |
| Zdroj: | Transplantation. 87:360-369 |
| ISSN: | 0041-1337 |
| Popis: | 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.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.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.These results indicate that in synergy with co-stimulation blockade, CXCR3 is a viable therapeutic target to prevent acute graft rejection. |
| Databáze: | OpenAIRE |
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