LONG-TERM ACCEPTANCE OF PORCINE PULMONARY ALLOGRAFTS WITHOUT CHRONIC REJECTION

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P1205 Aims: The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. Using a strategy developed in our laboratory to induce tolerance across strong allogeneic barriers, we have employed a brief, but intensive course of post-operative immunosuppression in order to determine whether the induction of donor-specific hyporesponsiveness would prevent allograft rejection in a preclinical model of lung transplantation using MHC-inbred miniature swine. Methods: Orthotopic left lung allografts were performed using MHC class I-disparate donors. The recipients received a 12-day post-operative course of cyclosporine (10-13 mg/kg/d [as a daily IV infusion over one hour]) (n = 6) or a 12-day post-operative course of tacrolimus (0.15 mg/kg/d [as a continuous IV infusion]) (n = 3) as their only immunosuppression. Control animals received no immunosuppression (n = 3). Results: Cyclosporine-treated recipients exhibited graft survival ranging from 67 to >605 days. All six animals developed acute cellular rejection between post-operative days (PODs) 27 and 108. Two animals lost their grafts on PODs 67 and 69, before developing chronic rejection. The other four recipients developed chronic rejection between PODs 119 and 238. In contrast, all tacrolimus-treated recipients maintained their grafts long term, without developing acute or chronic rejection (> 185, > 154, and > 77). These recipients also exhibited donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity. Furthermore, after priming with donor antigen, peripheral blood lymphocytes from all tacrolimus-treated recipients were able to suppress the response of naïve recipient-matched lymphocytes against donor and third-party antigen, suggesting of the presence of regulatory T cells. All untreated control animals lost their grafts to acute rejection by POD 11. Conclusions: This study demonstrates the ability of a brief post-operative course of tacrolimus to induce long-term graft acceptance and donor-specific hyporesponsiveness in a class I-disparate preclinical model. Moreover, a state of in vitro donor-specific hyporesponsiveness and the generation of regulatory T cells appear to accompany the induction of long-term graft acceptance. Finally, these data suggest that the induction of transplantation tolerance is a therapeutic strategy that is likely to abrogate both acute and chronic lung allograft rejection.