Prolonged, low-dose anti-thymocyte globulin, combined with CTLA4-Ig, promotes engraftment in a stringent transplant model.
Prolonged, low-dose anti-thymocyte globulin, combined with CTLA4-Ig, promotes engraftment in a stringent transplant model.
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DOI：
10.1371/journal.pone.0053797
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Najafian N
中科院分区：
文献类型：
--
作者：
D'Addio F;Boenisch O;Magee CN;Yeung MY;Yuan X;Mfarrej B;Vergani A;Ansari MJ;Fiorina P;Najafian N
尽管有显著的肾毒性，钙调磷酸酶抑制剂（CNIs）仍然是实体器官移植免疫抑制的基石。我们与其他人沿着报道了抗胸腺细胞球蛋白（ATG，Thymoglobulin®）的致耐受性，这通过其在体内使Tcl 3免于消耗和当以低的非消耗剂量施用时离体扩增Tcl 3的能力来证明。在肾移植受者中研究B7/CD 28阻断（LEA 29 Y，Belatacept）的临床试验证明，在选定人群中替代毒性CNI使用是可行的。兔多克隆抗鼠胸腺细胞球蛋白（mATG）与CTLA 4-IG联合作为诱导和/或延长的低剂量治疗，在严格的、完全MHC错配的鼠皮肤移植模型中进行给药，以评估移植物存活率和作用机制。延长的低剂量mATG与CTLA 4-IG组合可有效促进严格移植模型中的植入。我们的数据表明，mATG主要通过促进T细胞活化来实现移植物接受，而CTLA 4-IG通过在治疗的早期阶段限制效应T细胞库的活化和通过在维持阶段抑制抗兔抗体的产生来增强mATG功能，从而促进同种异体反应性的调节。这些数据为在人类移植受者中开发新的无CNI临床方案提供了依据。
Despite significant nephrotoxicity, calcineurin inhibitors (CNIs) remain the cornerstone of immunosuppression in solid organ transplantation. We, along with others, have reported tolerogenic properties of anti-thymocyte globulin (ATG, Thymoglobulin®), evinced by its ability both to spare Tregs from depletion in vivo and, when administered at low, non-depleting doses, to expand Tregs ex vivo. Clinical trials investigating B7/CD28 blockade (LEA29Y, Belatacept) in kidney transplant recipients have proven that the replacement of toxic CNI use is feasible in selected populations. Rabbit polyclonal anti-murine thymocyte globulin (mATG) was administered as induction and/or prolonged, low-dose therapy, in combination with CTLA4-Ig, in a stringent, fully MHC-mismatched murine skin transplant model to assess graft survival and mechanisms of action. Prolonged, low-dose mATG, combined with CTLA4-Ig, effectively promotes engraftment in a stringent transplant model. Our data demonstrate that mATG achieves graft acceptance primarily by promoting Tregs, while CTLA4-Ig enhances mATG function by limiting activation of the effector T cell pool in the early stages of treatment, and by inhibiting production of anti-rabbit antibodies in the maintenance phase, thereby promoting regulation of alloreactivity. These data provide the rationale for development of novel, CNI-free clinical protocols in human transplant recipients.
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