Posttransplant Inflammation Promotes Memory T Cell Recovery Following Antibody-Mediated Lymphoablation.

Abstract

Antibody-mediated depletion is commonly used as an induction therapy in recipients of organ transplants subjected to prolonged cold ischemia. We used a murine model of heart transplantation to test how surgery-induced inflammation and ischemia/reperfusion injury affect the reconstitution of recipient T cell repertoire after lymphoablation. We previously reported that preexisting memory T cells rapidly expand and contribute to transplant rejection in B6 recipients of BALB/c heart allografts treated with murine antithymocyte globulin (mATG). Unexpectedly, memory CD8 T cell recovery was not influenced by specificity for donor alloantigens suggesting an important role for posttransplant inflammation. In support of this, CD8 T cells recovered faster in B6 isograft recipients than in non-transplanted mice treated with mATG. The increase in cold ischemic time from 0.5 h (typical in mouse heterotopic heart transplantation model) to 8 h (more closely resembling clinical situations) markedly enhanced the post-depletion expansion of memory CD8 T cells in allograft recipients (10 fold increase at d. 7 and 10 posttransplant). To inhibit local and systemic posttransplant inflammation, we administered neutralizing anti-TNFa Ab into B6 recipients of BALB/c heart allografts treated with mATG or control rIgG. TNFa neutralization decreased the numbers of donor-reactive IFNg producing cells in the spleens of mATG treated recipient by 60%, but had little effect on the anti-donor IFNg response in control treated mice. These results suggest that TNFa facilitates recovery of the T cell repertoire rather than priming of donor-reactive T cells in recipients treated with mATG. Our data demonstrate that inflammation arising from surgical trauma, ischemia/reperfusion injury and lymphoablation facilitates memory T cell reconstitution following antibody-mediated depletion. Therefore, neutralizing proinflammatory cytokines may be used to improve the efficacy of induction therapies in sensitized transplant recipients.