PURPOSE: Durable transplantation tolerance has been achieved by the induction of mixed hematopoietic chimerism in a variety of animal models, including a fully allogeneic kidney transplant model at our own institution. Here, we sought to determine whether a similar approach could be applied to a non-human-primate lung allograft model.
METHODS: Using fully mismatched, ABO-compatible cynomolgus monkeys, three donor-recipient pairs underwent left orthotopic lung transplantation and bone marrow transplantation (3 × 108 cells/kg) after a non-myeloablative conditioning regimen. All pairs were disparate for the BW6 class I antigen and had a positive mixed lymphocyte reaction. The induction regimen consisted of total body irradiation (150 cGy; days -6 and –5); and thymic irradiation (700 cGy; day –1). Anti-thymocyte globulin (50 mg/kg; days -2, -1, and 0) and anti-CD40L monoclonal antibody (5c8; days 0, 2, 5, 7, 9, and 12) were administered. Cyclosporine (5-15mg/kg/d; days 0 through 27) was given. Chimerism was assessed by flow cytometry. Allografts were assessed by serial open lung biopsies and chest radiography. A fourth untreated donor-recipient pair served as a control.
RESULTS: Multi-lineage chimerism was established in all three recipients. Maximum percentage chimerism was 92.4%, 87.6%, and 87.5% (monocytes), 76.3%, 81.9%, and 93.8% (granulocytes) and 2.7%, 5.0%, and 9.6% (lymphocytes). All chimerism was transient, becoming undetectable by days 27, 34, and 53, respectively. Allograft survival was 34, 34, and 65 days, respectively. Histopathology confirmed acute cellular rejection in all three recipients. The untreated recipient lost its graft in 5 days due to acute rejection.
CONCLUSION: Transient multi-lineage chimerism was established in fully allogeneic non-human primate lung recipients; and all grafts survived considerably longer than the untreated control. However, compared to an analogous renal transplantation model in which half of all recipients demonstrated long-term graft acceptance without immunosuppression, the requirements for tolerance in lung transplantation appear to be more strict.
CLINICAL IMPLICATIONS: These data suggest that clinical lung transplantation tolerance may require the simultaneous induction of both central (deletional) and peripheral (regulatory) tolerance.
DISCLOSURE: James Allan, No Financial Disclosure Information; No Product/Research Disclosure Information