Results of Gal-Knockout Porcine Thymokidney Xenografts

Abstract

Clinical transplantation for the treatment of end-stage organ disease is limited by a shortage of donor organs. Successful xenotransplantation could immediately overcome this limitation. The development of homozygous a 1,3-galactosyltransferase knockout (GalT-KO) pigs removed hyperacute rejection as the major immunologic hurdle to xenotransplantation. Nevertheless, GalT-KO organs stimulate robust immunologic responses that are not prevented by immunosuppressive drugs. Murine studies show that recipient thymopoiesis in thymic xenografts induces xenotolerance. We transplanted life-supporting composite thymokidneys (composite thymus and kidneys) prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a preclinical xenotransplant model. Here, we report the results of seven xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole-body irradiation in all but one recipient. The regimen resulted in average recipient survival of over 50 days. This was associated with donor-specific unresponsiveness in vitro and early baboon thymopoiesis in the porcine thymus tissue of these grafts, suggesting the development of T-cell tolerance. The kidney grafts had no signs of cellular infiltration or deposition of IgG, and no grafts were lost due to rejection. These results show that xenogeneic thymus transplantation can support early primate thymopoiesis, which in turn may induce T-cell tolerance to solid organ xenografts.

Rituximab Treatment Prevents the Early Development of Proteinuria following Pig-to-Baboon Xeno-Kidney Transplantation

“…5,6 Baboons (Papio hamadryas) were purchased from Mannheimer Foundation (Homestead, FL). MGH Institutional Animal Care and Use Committee guidelines were followed.…”

“…6 Unfortunately, despite the achievement of immunologic hyporesponsiveness to pig antigens through a tolerance-inducing strategy using "thymokidney" grafts, 6 most of the recipients developed severe post-transplant proteinuria. Histologic studies showed slight glomerulopathy in the kidney grafts; electron microscopic examination indicated effacement of the foot processes of the podocytes even though the creatinine level was stable.…”

Immunological Challenges and Therapies in Xenotransplantation

“…This result was achieved by transplanting thymic tissue under the donor renal capsule (thymokidney) in recipients exposed to a protocol that included thymectomy, splenectomy, T-cell depletion, and whole-body irradiation. Doing without whole-body irradiation enabled a mean survival of more than 50 d. Thymic grafts supported thymopoiesis, and there was evidence of CD4 þ CD3 2 baboon cells adjacent to porcine thymic epithelial cells (Griesemer et al 2009). Donor-specific unresponsiveness with respect to the normal responses to allogeneic third parties was also detected in CTL assays.…”

“…Early studies on T-cell tolerance in mice showed that transplanting fetal or neonatal pig thymic tissue into thymectomized mice could induce a central tolerance of pig skin grafts (Zhao et al 1996). This strategy was successfully applied to the transplantation of GalT-KO pig kidneys into baboons, resulting in a normal renal function for up to 83 d (Yamada et al 2005;Griesemer et al 2009). This result was achieved by transplanting thymic tissue under the donor renal capsule (thymokidney) in recipients exposed to a protocol that included thymectomy, splenectomy, T-cell depletion, and whole-body irradiation.…”

Anti-Gal and Anti-Non Gal Antibody Barriers in Xenotransplantation

“…The thymus component of the xenograft is expected to tolerize the recipient against pig xenoantigens . Pig thymo-kidney xenografts that were transplanted into monkey recipients survived for almost 3 months, a much longer period than the survival period of kidney xenografts lacking the thymus component Griesemer et al, 2009).…”