Evidence for Human Thymopoiesis in a Porcine Thymus Graft and T Cell Tolerance to the Source Pig in a Human Recipient of a Thymokidney Xenotransplant 2254531

Abstract

Abstract Introduction Porcine thymic transplantation tolerizes xenogeneic recipients to the porcine source animal in animal models. A 54-year-old woman with complex comorbidities received a composite thymokidney transplant from an GGTA1 knockout pig, achieving initial renal function before xenograft failure for non-immunological reasons on postoperative day (POD) 47. Methods Serial peripheral blood mononuclear cell (PBMC) samples were analyzed by spectral FCM, and mixed lymphocyte reactions (MLRs) were performed on purified T cells to assess tolerance. Thymocytes were isolated from the thymic portion of the xenograft explant and analyzed using spectral FCM Results T cell levels in peripheral blood declined to 10/µL post-induction therapy and recovered to a peak of 342/µL by POD28. By POD21, 53% of the recovering CD4 T cells displayed a CD45RA+CCR7+ “naïve” phenotype and expressed CD31, consistent with recent thymic emigrants (RTEs). Pre-transplant CD4 T cells included 20.8% RTEs (Figure 1A). FCM analysis on cells from the POD47 thymic xenograft revealed human CD45+ leukocytes (0.53%), including double-positive (CD4+CD8+), single-positive, and double-negative thymocytes. The double-negative cells expressed markers such as CD5, CD7, CD1a, and CD34, consistent with human T cell progenitors in the porcine thymus (Figure 1B). MLR results demonstrated progressive hyporesponsiveness toward the source pig with preserved responses to third-party pig and allogeneic human cells, achieving full donor-specific unresponsiveness by POD47 and POD86 (Figure 1C). Conclusion These findings suggest that a porcine thymus in a thymokidney xenograft supported human thymopoiesis and the development of T cells tolerant to the pig. Thymic transplantation is a promising approach to achieving T cell tolerance in xenotransplant recipients Funding Source n/a Topic Categories Transplantation Immunology (TRAN)