Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Am J Transplant. 2009 Dec;9(12):2669-78. doi: 10.1111/j.1600-6143.2009.02849.x. Epub 2009 Oct 21.
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 alpha1,3-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.
临床移植治疗终末期器官疾病受到供体器官短缺的限制。成功的异种移植可以立即克服这一限制。纯合 alpha1,3-半乳糖基转移酶敲除（GalT-KO）猪的发展消除了超急性排斥反应，这是异种移植的主要免疫障碍。然而，GalT-KO 器官会引起强烈的免疫反应，免疫抑制药物无法预防。鼠类研究表明，受体胸腺在异种胸腺移植物中的发生诱导了异种耐受。我们将在 GalT-KO 小型猪中制备的具有生命支持作用的复合胸腺肾（复合胸腺和肾脏）移植到狒狒中，试图在临床前异种移植模型中诱导耐受。在这里，我们报告了使用无类固醇免疫抑制方案进行的七次异种复合胸腺移植的结果，该方案除了一名受者外，均排除了全身照射。该方案导致受者平均存活时间超过 50 天。这与体外供体特异性无反应性以及这些移植物中猪胸腺组织中的早期狒狒胸腺发生有关，表明 T 细胞耐受的发展。肾移植物没有细胞浸润或 IgG 沉积的迹象，也没有移植物因排斥而丢失。这些结果表明异种胸腺移植可以支持早期灵长类动物的胸腺发生，这反过来可能诱导对实体器官异种移植物的 T 细胞耐受。
