Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells.
Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells.
复制标题
整合素拮抗剂可防止 CD8(+) 记忆 T 细胞引起的共刺激阻滞抵抗性移植排斥。
DOI：
10.1111/j.1600-6143.2011.03762.x
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Ford ML
中科院分区：
文献类型：
--
作者：
Kitchens WH;Haridas D;Wagener ME;Song M;Kirk AD;Larsen CP;Ford ML
belatacept在后期临床试验中的成功开创了一类基于共刺激阻断的新型免疫抑制剂的到来，共刺激阻断是一种破坏同种异体反应性T细胞活化所需的基本信号的免疫抑制策略。尽管肾功能得到改善，但接受贝拉西普治疗的肾移植受者的急性排斥反应发生率增加。这一发现使人们重新关注共刺激阻断抵抗性排斥反应，特别是同种异体反应性记忆T细胞在介导这种抵抗中的作用。为了研究共刺激阻断抵抗性排斥反应的机制并提高共刺激阻断的临床疗效，我们开发了一种模拟供体特异性记忆性CD 8 + T细胞应答的实验移植系统。在确认移植物特异性记忆T细胞介导共刺激阻断抵抗性排斥反应后，我们描述了整合素在这种排斥反应中的作用。当共刺激阻断与抗VLA-4或抗LFA-1偶联时，记忆T细胞对共刺激阻断的抗性被废除。机制研究表明，在共刺激阻断的存在下，抗VLA-4损害T细胞向移植物的运输，但不损害记忆T细胞回忆效应子功能，而抗LFA-1减弱运输和记忆回忆效应子功能。由于针对这些整合素的拮抗剂在临床上获得批准，这些发现可能对未来的临床移植试验具有重要的转化潜力。
The success of belatacept in late-stage clinical trials inaugurates the arrival of a new class of immunosuppressants based on costimulatory blockade, an immunosuppression strategy that disrupts essential signals required for alloreactive T cell activation. Despite having improved renal function, kidney transplant recipients treated with belatacept experienced increased rates of acute rejection. This finding has renewed focus on costimulatory blockade-resistant rejection and specifically the role of alloreactive memory T cells in mediating this resistance. To study mechanisms of costimulatory blockade-resistant rejection and enhance the clinical efficacy of costimulatory blockade, we developed an experimental transplant system that models a donor-specific memory CD8+ T cell response. After confirming that graft-specific memory T cells mediate costimulatory blockade-resistant rejection, we characterized the role of integrins in this rejection. The resistance of memory T cells to costimulatory blockade was abrogated when costimulatory blockade was coupled with either anti-VLA-4 or anti-LFA-1. Mechanistic studies revealed that in the presence of costimulatory blockade, anti-VLA-4 impaired T cell trafficking to the graft but not memory T cell recall effector function, whereas anti-LFA-1 attenuated both trafficking and memory recall effector function. As antagonists against these integrins are clinically approved, these findings may have significant translational potential for future clinical transplant trials.
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影响因子：
8.8
作者：
Augustine, JJ;Siu, DS;Hricik, DE
通讯作者：
Hricik, DE
DOI：
10.1385/ijgc:26:1:23
发表时间：
1999-08-01
期刊：
INTERNATIONAL JOURNAL OF PANCREATOLOGY
影响因子：
--
作者：
Arai, K;Sunamura, M;Matsuno, S
通讯作者：
Matsuno, S
DOI：
10.1084/jem.194.2.219
发表时间：
2001-07-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Henderson RB;Lim LH;Tessier PA;Gavins FN;Mathies M;Perretti M;Hogg N
通讯作者：
Hogg N
影响因子：
20.3
作者：
Amir, Avital L.;D'Orsogna, Lloyd J. A.;Heemskerk, Mirjam H. M.
通讯作者：
Heemskerk, Mirjam H. M.
影响因子：
15.9
作者：
Badell, Idelberto R.;Russell, Maria C.;Larsen, Christian P.
通讯作者：
Larsen, Christian P.