Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from α1, 3-galactosyltransferase gene-knockout pigs in baboons
Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from α1, 3-galactosyltransferase gene-knockout pigs in baboons
复制标题
DOI：
10.2353/ajpath.2008.070672
复制
发表时间：
2008-06-01
影响因子：
6
通讯作者：
Colvin, Robert B.
中科院分区：
文献类型：
--
作者：
Shimizu, Akira;Hisashi, Yosuke;Colvin, Robert B.
进行了从α 1，3-半乳糖基转移酶基因敲除（GalT-KO）猪到狒狒的异位心脏异种移植，以表征在不存在抗Gal抗体介导的排斥反应的情况下对异种移植物的免疫反应。八只狒狒接受来自GalT-KO猪供体的异位心脏异种移植物。所有狒狒均接受慢性免疫抑制治疗。对活检和移植物切除术样本进行组织学和免疫组织化学研究。无超急性排斥反应。三只狒狒在移植后16至56天被安乐死或死亡。其他5个移植物在第59 - 179天（中位数，78天）之间停止跳动。所有失败的移植物表现出血栓性微血管病（TM），微血管中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与免疫球蛋白（IgM和IgG）和补体（C3、C4d和C5 b-9）沉积的增加以及随后TUNEL+内皮细胞死亡和促凝血激活（组织因子和血管性血友病因子表达增加和CD 39表达减少）的增加平行发生。所有移植物中均存在CD 3（+）T细胞浸润，且与TM的发生弱相关。总之，尽管使用GalT-KO猪供体防止了超急性排斥反应并延长了移植物存活，但缓慢进行性体液排斥反应（可能与异种移植物的非Gal抗体有关）和血栓调节紊乱是异种移植物长期存活的主要免疫障碍。
Heterotopic cardiac xenotransplantation from alpha 1,3-galactosyltransferase gene-knockout (GalT-KO) swine to baboons was performed to characterize immunological 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 immunosuppressive therapy. Both histological and immunohistochemical studies were performed on biopsy and graftectomy samples. No hyperacute rejection was observed. Three baboons were euthanized or died 16 to 56 days after transplantation. The other five grafts ceased beating between days 59 and 179 (median, 78 days). 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 procoagulant activation (increased expression of both tissue factor and von Willebrand factor and decreased expression of CD39). CD3(+) T-cell infiltration occurred in all grafts and weakly correlated with the development of TM. in conclusion, although the use of GalT-KO swine donors prevented hyperacute rejection and prolonged graft survival, slowly progressive humoral rejection-probably associated with non-Gal antibodies to the xenograft-and disordered thromboregulation represent major immunological barriers to long-term xenograft survival.