Porcine kidney and heat transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption
Porcine kidney and heat transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption
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DOI：
10.1097/00007890-199901150-00004
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发表时间：
1999-01-15
期刊：
影响因子：
6.2
通讯作者：
Sachs, DH
中科院分区：
文献类型：
--
作者：
Kozlowski, T;Shimizu, A;Sachs, DH
背景异种移植将为解决目前移植器官短缺的问题提供一个办法。我们的研究小组已经成功地在小鼠和猴同种异体移植模型中诱导耐受。本研究试图将相同的耐受诱导方案扩展到猪-狒狒器官移植模型。9只狒狒接受了预处理方案（包括非清髓性或清髓性全身和胸腺照射、脾切除术、抗胸腺细胞球蛋白、药物免疫抑制和猪骨髓移植[BMTx]），先前已证明该方案可诱导猴的供体特异性同种异体移植耐受。此外，进行抗α Gal抗体（Ab）的免疫吸附。九只狒狒中有四只接受了猪肾移植（KTx），一只还接受了SLA匹配肾脏的重复移植。其中2例接受了异位猪心移植（HTx）。三只狒狒进行了长期的研究自然抗体kinetic.Results，在三只狒狒，没有器官移植，免疫吸附，接受了调理方案，约90%的抗体减少，但抗体恢复到预处理水平或更高的天然抗体kinetic. Results的长期研究。相反，器官移植后抗体水平仍然很低。在BMTx、KTx或HTx之前或之后，在任何狒狒中均未检测到除α Gal以外的猪抗原抗体。无移植物死于超急性排斥反应。KTx功能在3-6天内开始恶化，少尿和血尿进展为无尿，分别在3、6、9、11和14天后切除肾脏。一只HTx在第8天停止运作;第二只狒狒在第15天死于HTx感染。在所有6只移植狒狒中均出现凝血病和血小板减少症特征（大腿D二聚体、凝血酶原时间和部分凝血活酶时间延长以及纤维蛋白原下降），导致2只狒狒出现严重出血并发症，其中1只狒狒在第9天死亡。供体器官显示进行性急性体液排斥反应伴IgM、IgG和补体沉积;还观察到局灶性单核细胞浸润。输尿管是KTx受排斥反应影响的最早结构，并进展为坏死。这种预处理方案防止了超急性排斥反应，但在防止Ab返回方面无效，Ab返回与具有凝血功能障碍的急性体液排斥反应的发展相关。除α-半乳糖抗体外，没有狒狒产生抗猪抗体。需要进一步修改针对抑制Ab产生的方案，以成功诱导狒狒对猪器官的耐受性。
Background. Xenotransplantation would provide a solution to the current shortage of organs for transplantation. Our group has been successful in inducing tolerance in mice and monkey models of allogeneic transplantation. The present study attempts to extend the same tolerance-inducing regimen to a pig-to-baboon organ transplantation model.Methods. Nine baboons underwent a conditioning regimen (consisting of nonmyeloablative or myeloablative whole body and thymic irradiation, splenectomy, antithymocyte globulin, pharmacologic immunosuppression and porcine bone marrow transplantation [BMTx]), which has previously been demonstrated to induce donor-specific allograft tolerance in monkeys. In addition, immunoadsorption of anti-alpha Gal antibody (Ab) was performed. Four of the nine baboons received pig kidney transplants (KTx), and one also underwent repeat transplantation with an SLA-matched kidney. Two received heterotopic pig heart transplants (HTx). Three baboons underwent conditioning without organ transplantation for long-term studies of natural Ab kinetics.Results, In the three baboons that received the conditioning regimen without an organ transplant, immunoadsorption reduced Ab by approximately 90%, but recovery of Ab to pretreatment level or higher occurred within 7 days. In contrast, the level of Ab remained low after organ transplant. No Ab to pig antigens other than alpha Gal was detected in any baboon before or after BMTx, KTx, or HTx. No graft succumbed to hyperacute rejection. KTx function began to deteriorate within 3-6 days, with oliguria and hematuria progressing to anuria, and the kidneys were excised after 3, 6, 9, 11, and 14 days, respectively. One HTx ceased functioning at 8 days; the second baboon died with a contracting HTx at 15 days. Features of coagulopathy and thrombocytopenia developed in all six transplanted baboons thigh D dimer, prolonged prothrombin time and partial thromboplastin time, and falling fibrinogen) resulting in serious bleeding complications in two baboons, one of which died on day 9, Donor organs showed progressive acute humoral rejection with deposits of IgM, IgG, and complement; a focal mononuclear cellular infiltrate was also observed. The ureter was the earliest structure of the KTx affected by rejection, with progression to necrosis.Conclusions. This conditioning regimen prevented hyperacute rejection but was ineffective in preventing the return of Ab, which was associated with the development of acute humoral rejection with features of coagulopathy. No baboon developed anti-pig Ab other than alpha Gal Ab. Further modifications of the protocol directed toward suppression of production of Ab are required to successfully induce tolerance to pig organs in baboons.