Thymic transplantation in miniature swine. II. Induction of tolerance by transplantation of composite thymokidneys to thymectomized recipients

Previous studies in our laboratory have demonstrated that the presence of t he thymus is essential for rapid and stable tolerance induction in allotran splant models. We now report an attempt to induce tolerance to kidney allog rafts by transplanting donor thymic grafts simultaneously with the kidney i n thymectomized recipients. Recipients were thymectomized 3 wk before recei ving an organ and/or tissues from a class I-mismatched donor. Recipients re ceived 1) a kidney allograft alone, 2) a composite allogeneic thymokidney ( kidney with vascularized autologous thymic tissue under its capsule), or 3) separate kidney and thymic grafts from the same donor. All recipients rece ived a 12-day course of cyclosporine, Thymectomized animals receiving a kid ney allograft alone or receiving separate thymic and kidney grafts had unst able renal function due to severe rejection with the persistence of anti-do nor cytotoxic T cell reactivity, In contrast, recipients of composite thymo kidney grafts had stable renal function with no evidence of rejection histo logically and donor-specific unresponsiveness. By postoperative day 14, the thymic tissue in the thymokidney contained recipient-type dendritic cells. By postoperative day 60, recipient-type class I positive thymocytes appear ed in the thymic medulla, indicating thymopoiesis, T cells were both recipi ent and donor MHC-restricted. These data demonstrate that the presence of v ascularized-donor thymic tissue induces rapid and stable tolerance to class I- disparate kidney allografts in thymectomized recipients. To our knowled ge, this is the first evidence of functional vascularized thymic grafts per mitting transplantation tolerance to be induced in a large animal model.