The mechanisms of graft failure in cardiac xenografts from α1,3-galactosyltransferase, gene-knockout (GalT-KO) pigs in babooons

从α1，3-半乳糖基转移酶基因敲除的猪(GalT-KO)进行了异位心脏移植。在没有抗Gal抗体介导的排斥反应的情况下，对Galt-K0异种心脏移植的病理学进行了评估，以表征异种移植的免疫反应。8只狒狒接受了来自Galt-KO猪供体的异位心脏移植。所有的狒狒都接受了慢性免疫抑制治疗。对活检和移植物切除标本进行组织学和免疫组织化学研究。无超急性排斥反应发生。移植后16至56天，3只狒狒被安乐死或死亡。其余5支移植物在59~179天(中位数78天)停止搏动。所有失败的移植物都表现为血栓性微血管病(TM)，微血管内有富含血小板的纤维蛋白血栓，心肌缺血和坏死，以及局灶性间质出血。TM的发生与免疫球蛋白(IgM和Ig G)和补体(C3、C4d和C5b-9)沉积的增加以及随后TUNEL内皮细胞死亡和内皮细胞促凝血剂激活(组织因子和von Willebrand因子的表达增加，CD39的表达降低)同步发展。所有移植物均有CD3T细胞浸润。缓慢进行性体液排斥，可能与诱发的非半乳糖抗体相关，以及可能的血栓调节紊乱，是异种移植长期存活的主要免疫障碍，即使使用Galt-KO猪供者也是如此。此外，在慢性免疫抑制的维持下，移植物也发生了急性异种细胞排斥反应和慢性排斥反应。

Heterotopic cardiac xenotransplantation from α1,3-galactosyltransferase gene-knockout (GalT-KO) swine to baboons has been performed. The pathology of the GalT-K0 cardiac xenografts was assessed to characterize the immunologic reaction to the xenograft in the absence of anti-Gal antibody-mediated rejection.Eight baboons received heterotopic cardiac xenografts from GalT-KO porcine donors. All baboons were treated with chronic immunosuppression. Histologic and immunohistochemical studies were performed on biopsy and graftectomy samples. No hyperacute rejection occurred. Three baboons were euthanized or died 16 to 56 days after transplantation. The other 5 grafts ceased beating between days 59 and 179 (median 78). All failing grafts exhibited thrombotic microangiopathy (TM) with platelet-rich fibrin thrombi in the microvasculature, myocardial ischemia and necrosis, and focal interstitial hemorrhage. TM developed in parallel with increases in immunoglobulin (IgM and IgG) and complement (C3, C4d, and C5b-9) deposition, as well as with subsequent increases in both TUNEL+ endothelial cell death and endothelial cell procoagulant activation (increased expression of tissue factor and von Willebrand factor, with concomitant decreased expression of CD39). CD3+T cell infiltration occurred in all grafts. Slowly progressive humoral rejection, likely associated with elicited nonGal antibodies, and possibly disordered thromboregulation represents a major remaining immunologic barrier to long-term xenograft survival, even when using GalT-KO swine donors. In addition, acute cellular xenograft rejection and chronic rejection also developed in grafts, maintained by chronic immunosupression.