Pretransplant Antithymocyte Globulin Has Increased Efficacy in Controlling Donor-Reactive Memory T Cells in Mice
Pretransplant Antithymocyte Globulin Has Increased Efficacy in Controlling Donor-Reactive Memory T Cells in Mice
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DOI：
10.1111/ajt.12068
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发表时间：
2013-03-01
影响因子：
8.8
通讯作者：
Valujskikh, A.
中科院分区：
文献类型：
--
作者：
Ayasoufi, K.;Yu, H.;Valujskikh, A.
抗体介导的淋巴细胞耗竭常用作致敏移植患者的诱导治疗。尽管在人类移植受者中，在淋巴消融治疗后仍能检测到具有效应/记忆表型的T细胞，但对预先存在的供体反应性记忆在淋巴消融后T细胞库重建和同种免疫应答诱导中的作用知之甚少。我们表明，在小鼠心脏移植模型中，兔抗小鼠胸腺细胞球蛋白（mATG）治疗后的抗供体免疫反应占主导地位的T细胞来自预先存在的记忆舱。移植前1周给予mATG（pre-TP）在靶向预先存在的供体反应性记忆T细胞、抑制总体抗供体T细胞反应和延长心脏移植物存活方面比移植时常用的治疗（peri-TP）更有效。peri-TP mATG控制抗供体记忆应答的失败是由于预先存在的记忆T细胞的更快恢复而不是它们的低效耗尽。这种快速恢复并不依赖于T细胞对供体同种异体抗原的特异性，这表明移植后炎症在这一过程中起着重要作用。我们的研究结果提供了深入了解淋巴消融术后剩余的同种免疫反应的组成部分，并可能有助于指导未来在致敏移植受者中使用ATG。
Antibody-mediated lymphocyte depletion is frequently used as induction therapy in sensitized transplant patients. Although T cells with an effector/memory phenotype remain detectable after lymphoablative therapies in human transplant recipients, the role of preexisting donor-reactive memory in reconstitution of the T cell repertoire and induction of alloimmune responses following lymphoablation is poorly understood. We show in a mouse cardiac transplantation model that antidonor immune responses following treatment with rabbit antimouse thymocyte globulin (mATG) were dominated by T cells derived from the preexisting memory compartment. Administration of mATG 1 week prior to transplantation (pre-TP) was more efficient in targeting preexisting donor-reactive memory T cells, inhibiting overall antidonor T cell responses, and prolonging heart allograft survival than the commonly used treatment at the time of transplantation (peri-TP). The failure of peri-TP mATG to control antidonor memory responses was due to faster recovery of preexisting memory T cells rather than their inefficient depletion. This rapid recovery did not depend on T cell specificity for donor alloantigens suggesting an important role for posttransplant inflammation in this process. Our findings provide insights into the components of the alloimmune response remaining after lymphoablation and may help guide the future use of ATG in sensitized transplant recipients.