Cozzi Emanuele, Vial Conrad, Ostlie Daniel, Farah Bhatti, Chavez Gilda, Smith Kenneth G C, Bradley John R, Thiru Sathia, Davies Hugh F S, Wallwork John, White David J G, Goddard Martin, Friend Peter J
Transplant Unit, Imutran Ltd (A Novartis Pharma AG Company), Cambridge, UK.
Xenotransplantation. 2003 Jul;10(4):300-10. doi: 10.1034/j.1399-3089.2003.02014.x.
To date, the best results in life-supporting pig-to-primate renal xenotransplantation have been obtained in recipients exposed to long-term immunosuppression with cyclophosphamide. As this agent is frequently associated with side-effects, we have explored the potential of a mycophenolate sodium-based maintenance immunosuppression in this model. Human decay-accelerating factor (hDAF) transgenic kidneys were transplanted into splenectomized and bilaterally nephrectomized cynomolgus monkeys immunosuppressed with mycophenolate sodium, cyclosporin A and steroids, and exposed to a brief induction course with cyclophosphamide (up to four doses). After transplantation, the primates were monitored daily for biochemical and haematological evaluations and for the measurements of haemolytic anti-pig antibodies (APA). A detailed histological analysis of each explanted graft was also performed. All the animals showed very poor initial graft function but survived for up to 51 days. In contrast to our previous studies in xenograft recipients on long-term immunosuppression with cyclophosphamide, minimal or no circulating xeno-directed antibodies, as measured by the evaluation of APA titres, were detected in this series although some degree of acute humoral rejection was observed in all the explanted grafts and was the primary cause of graft failure. Furthermore, in addition to areas of humorally mediated graft damage, we have observed for the first time areas with exclusive and prominent infiltration by CD2+ and CD8+ mononuclear cells presenting patterns compatible with tubulitis, glomerulitis and arteritis, which we have called acute cellular xenograft rejection (ACXR). In addition, CD68+ infiltrating macrophages and CD20+ B-cells were also present. This study demonstrates that a triple maintenance immunosuppression with mycophenolate sodium, cyclosporin A and steroids is a viable alternative to a cyclophosphamide-based immunosuppression to obtain prolonged survival of porcine organs transplanted into primates. However, a more stringent control of antibody forming cells remains essential to further extend the survival of xenografts in this model. In addition, the use of the immunosuppressive regimen reported here in the primate is associated with the occurrence of a new category of cell-mediated xenograft injury (ACXR) whose significance has yet to be clarified.
迄今为止，在接受环磷酰胺长期免疫抑制的受体中，实现了支持生命的猪到灵长类动物肾异种移植的最佳结果。由于这种药物常伴有副作用，我们在该模型中探索了基于麦考酚钠的维持性免疫抑制的潜力。将人衰变加速因子（hDAF）转基因肾移植到经麦考酚钠、环孢素A和类固醇免疫抑制的脾切除和双侧肾切除的食蟹猴体内，并给予环磷酰胺短暂诱导疗程（最多四剂）。移植后，每天对灵长类动物进行生化和血液学评估以及溶血抗猪抗体（APA）测量。还对每个移植肾进行了详细的组织学分析。所有动物最初的移植肾功能都很差，但存活了长达51天。与我们之前对接受环磷酰胺长期免疫抑制的异种移植受体的研究不同，本系列研究中通过评估APA滴度检测到的循环异种定向抗体极少或未检测到，尽管在所有移植肾中均观察到一定程度的急性体液排斥反应，且这是移植失败的主要原因。此外，除了体液介导的移植损伤区域外，我们首次观察到CD2 +和CD8 +单核细胞出现排他性且显著浸润的区域，呈现出与肾小管炎、肾小球炎和动脉炎相符的模式，我们将其称为急性细胞异种移植排斥（ACXR）。此外，还存在CD68 +浸润巨噬细胞和CD20 + B细胞。本研究表明，麦考酚钠、环孢素A和类固醇三联维持性免疫抑制是基于环磷酰胺的免疫抑制的可行替代方案，可使移植到灵长类动物体内的猪器官获得更长的存活时间。然而，更严格地控制抗体形成细胞对于进一步延长该模型中异种移植的存活时间仍然至关重要。此外，在灵长类动物中使用此处报道的免疫抑制方案与一种新的细胞介导的异种移植损伤（ACXR）的发生有关，其意义尚待阐明。
