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Results of Gal-Knockout Porcine Thymokidney Xenografts

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Results of Gal-Knockout Porcine Thymokidney Xenografts Results of Gal-Knockout Porcine Thymokidney Xenografts The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Griesemer, A. D., A. Hirakata, A. Shimizu, S. Moran, A. Tena, H. Iwaki, Y. Ishikawa, et al. 2009. “Results of Gal-Knockout Porcine Thymokidney Xenografts.” American Journal of Transplantation 9 (12) (December): 2669–2678. doi:10.1111/j.1600-6143.2009.02849.x. Published Version doi:10.1111/j.1600-6143.2009.02849.x Citable link https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37364476 Terms of Use This article was downloaded from Harvard University’s DASH repository, WARNING: This file should NOT have been available for downloading from Harvard University’s DASH repository.;This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/ urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA NIH Public Access Author Manuscript Am J Transplant. Author manuscript; available in PMC 2010 November 20. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Am J Transplant. 2009 December ; 9(12): 2669±2678. doi:10.1111/j.1600-6143.2009.02849.x. Results of Gal-Knockout porcine thymokidney xenografts Adam D. Griesemer1, Atsushi Hirakata1, Akira Shimizu1, Shannon Moran1, Aseda Tena1, Hideyuki Iwaki1, Yoshinori Ishikawa1, Patrick Schule1, J. Scott Arn1, Simon C. Robson2, Jay A. Fishman3, Megan Sykes1, David H. Sachs1, and Kazuhiko Yamada1,4 1Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 2Transplant Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 3Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 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 α1,3-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 prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a pre-clinical xenotransplant model. Here, we report the results of 7 xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole body irradiation in all but 1 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 human thymopoiesis, which in turn may induce T cell tolerance to solid organ xenografts. Keywords Xenotransplantation; Baboon; GalT-KO; Thymus; Life-supporting renal grafts Introduction Despite recent advances in the field of transplantation, there remains a large discrepancy between the number of patients that could benefit from transplantation and the number of available donor organs. Recently, techniques for reprogramming adult cells by gene transduction to produce pluriopotent stem cells have renewed interest in the possibility of tissue regeneration for organ repair while avoiding ethical issues associated with embryonic cell use(1). A recent report on the generation of rat hearts from stem cells noted that these 4Address all correspondence to: Kazuhiko Yamada, M.D. PhD., MGH-East; 13th Street, CNY-149, 9019; Boston, MA 02129. Head, Organ Transplantation Tolerance and Xenotransplantation Lab. Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, USA, [email protected]. Griesemer et al. Page 2 structures expressed only 2% of the functional capacity of a normal rat heart(2). Such results indicate that this technology needs significant development before preclinical testing. NIH-PA Author Manuscript NIH-PA Author ManuscriptTherefore, NIH-PA Author Manuscript xenotransplantation of solid organs remains at the forefront of the search for a solution to the organ shortage. The pig is generally considered the most suitable donor species for xenotransplantation(3). Previously, the major obstacle preventing successful transplantation of porcine organs into primates was the existence of natural antibodies against a terminal saccharide epitope, galactose-α1,3-galactose (Gal), produced by α1,3-galactosyltransferase (GalT)(4). While this gene is functional in pigs, it is not functional in Old World monkeys and humans. These antibodies comprise over 70% of preformed primate anti-pig antibody activity(3). Transplants performed across this barrier result in antibody-mediated graft rejection. The generation of homozygous GalT knockout (GalT-KO) pigs in 2002(5–7) removed this barrier to solid organ xenotransplantation. Utilizing GalT-KO pigs as donors, we and others reported studies of life-supporting kidney xenografts in baboons receiving chronic immunosuppression(8,9). While these grafts did not undergo hyperacute rejection, outcomes were not significantly better than those achieved using kidneys from pigs overexpressing human decay accelerating factor (hDAF)(10–12), indicating that additional strategies are required to achieve the clinical application of xenotransplantation. We have shown that xenogeneic T cell responses between pigs and humans are at least as strong as allogeneic responses in vitro(13,14). Because T cells enhance B cell and NK cell activity in vivo, xenogeneic cellular responses are generally stronger than allogeneic cellular responses. In vivo, we have shown cellular infiltrates with antibody deposits in rejected GalT-KO kidneys(8). Others have reported rapid and complete rejection of GalT-KO kidneys with the development of high levels of induced non-Gal anti-Ab, including IgG, which is likely due to T cell activation(9). All these results support the importance of using a T cell tolerance strategy in xenotransplantation. We have previously shown that co-transplantation of porcine thymus tissue as a vascularized graft can induce tolerance across full allogeneic barriers to kidneys and hearts in a miniature swine model(15–17). Moreover, xenogeneic tolerance can be achieved via thymic xenotransplantation in mice and humanized mouse models(18–20). When this strategy was applied in the pig-to-baboon model using hDAF composite thymus and kidney (thymokidney) grafts, the kidneys were rejected due to anti-Gal antibodies by day 29, although there was clear evidence for T cell unresponsiveness in vitro(21). Using GalT-KO donors, which eliminate humoral rejection by anti-Gal antibodies, a survival advantage was conferred by the vascularized thymus graft, resulting in life-supporting renal xenograft survival up to 83 days with normal creatinine levels(8). However, the initial immunosuppressive regimens used to facilitate the induction of tolerance by the thymus grafts included administration of steroids and whole body irradiation (WBI) and were associated with a high incidence of early post-operative complications, mainly infectious in nature, which decreased average survival to 34 days(8). In order to develop a more clinically applicable regimen, we have now eliminated whole body irradiation and corticosteroids from the treatment protocol. Here, we report that the modified protocol resulted in an average survival greater than 50 days, and no graft was lost due to rejection. Additionally, for the first time we were able to demonstrate that the porcine thymus tissue supported early baboon thymopoiesis. This finding was associated with donor-specific unresponsiveness in vitro. Histological analysis revealed no signs of cellular infiltration or deposition of IgG. These results suggest that vascularized thymus tissue transplantation may be able to induce tolerance across the xenogeneic barrier and represent a step toward clinical application of this strategy. Am J Transplant. Author manuscript; available in PMC 2010 November 20. Griesemer et al. Page 3 Materials and Methods Animals NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript All animals were cared for according to the guidelines of the Massachusetts General Hospital Institutional Animal Care and Use Committee. Recipient baboons (Papio hamadryus, n=7) weighing 7 to 12 kg were purchased from Mannheimer Foundation, Homestead, FL. Xenogeneic organs were obtained from by GalT-KO miniature swine (n=7) weighing 9 to 27 kg. The generation of these animals has been published previously(6). All pigs were produced from either GalT-KO homozygous × heterozygous or homozygous × homozygous breeding (22). Surgery (a) Thymokidney preparation—Seven thymokidneys were prepared by implantation of autologous thymic tissue under the kidney capsule as previously described (23). (b) Recipient preparation—All operations were performed under general
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