Cardiac xenografts show reduced survival in the absence of transgenic human thrombomodulin expression in donor pigs
Cardiac xenografts show reduced survival in the absence of transgenic human thrombomodulin expression in donor pigs
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DOI：
10.1111/xen.12465
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发表时间：
2019-03-01
影响因子：
3.9
通讯作者：
Mohiuddin, Muhammad M.
中科院分区：
文献类型：
--
作者：
Singh, Avneesh K.;Chan, Joshua L.;Mohiuddin, Muhammad M.
供体器官的遗传操作和靶向特异性免疫抑制的组合有助于实现心脏异种移植物的长期存活。最近，我们的临床前猪-狒狒异位心脏异种移植模型的结果表明，三管齐下的方法成功地延长了异种移植物的存活：（a）供体猪α-1，3-半乳糖基转移酶（Gal）基因敲除（GTKO）以防止Gal特异性抗体介导的排斥反应;（B）人补体调节蛋白的转基因表达（hCRP; hCD 46）和人血栓调节蛋白血栓调节蛋白（hTBM）以避免补体激活和凝血失调;和（c）有效诱导和维持免疫调节，特别是通过用抗CD 40（2C 10 R4）单克隆抗体（mAb）共刺激阻断CD 40-CD 40 L途径。使用这种操作组合，我们报告了心脏异种移植物存活率的显著改善。在本研究中，我们报告了接受来自不表达hTBM（GTKO.CD46）的猪的异种移植物的心脏异种移植受体（n = 3）的存活率。我们观察到，所有移植物在早期时间点（中位数70天）发生排斥反应，尽管利用我们以前报道的成功的免疫抑制方案和非半乳糖抗体反应的有效控制。这些结果支持我们的假设，即在供体猪中转基因表达人血栓调节蛋白在基于共刺激阻断的免疫调节方案的设置中赋予异种移植物存活的独立保护作用。
A combination of genetic manipulations of donor organs and target-specific immunosuppression is instrumental in achieving long-term cardiac xenograft survival. Recently, results from our preclinical pig-to-baboon heterotopic cardiac xenotransplantation model suggest that a three-pronged approach is successful in extending xenograft survival: (a) alpha-1,3-galactosyl transferase (Gal) gene knockout in donor pigs (GTKO) to prevent Gal-specific antibody-mediated rejection; (b) transgenic expression of human complement regulatory proteins (hCRP; hCD46) and human thromboregulatory protein thrombomodulin (hTBM) to avoid complement activation and coagulation dysregulation; and (c) effective induction and maintenance of immunomodulation, particularly through co-stimulation blockade of CD40-CD40L pathways with anti-CD40 (2C10R4) monoclonal antibody (mAb). Using this combination of manipulations, we reported significant improvement in cardiac xenograft survival. In this study, we are reporting the survival of cardiac xenotransplantation recipients (n = 3) receiving xenografts from pigs without the expression of hTBM (GTKO.CD46). We observed that all grafts underwent rejection at an early time point (median 70 days) despite utilization of our previously reported successful immunosuppression regimen and effective control of non-Gal antibody response. These results support our hypothesis that transgenic expression of human thrombomodulin in donor pigs confers an independent protective effect for xenograft survival in the setting of a co-stimulation blockade-based immunomodulatory regimen.