Belatacept-Resistant Rejection Is Associated With CD28(+) Memory CD8 T Cells.
Belatacept-Resistant Rejection Is Associated With CD28(+) Memory CD8 T Cells.
复制标题
抗Belatacept的排斥反应与CD28（+）内存CD8 T细胞有关。
DOI：
10.1111/ajt.14349
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Adams AB
中科院分区：
文献类型：
--
作者：
Mathews DV;Wakwe WC;Kim SC;Lowe MC;Breeden C;Roberts ME;Farris AB;Strobert EA;Jenkins JB;Larsen CP;Ford ML;Townsend R;Adams AB
最近，新的治疗方法被设计成更特异性地靶向排斥反应，以提高疗效并限制不必要的毒性。Belatacept是一种CD 28-CD 80/86特异性试剂，与传统疗法相比，具有上级患者存活率和移植物功能，但其作为主要免疫抑制疗法的采用已受到排斥率增加的影响。在贝拉西普被广泛应用之前，阐明与这种排斥相关的潜在机制是至关重要的。为此，我们设计了一项在非人灵长类动物肾移植模型中进行的研究，其中动物接受了基于贝拉西普或他克莫司的免疫抑制方案治疗。有趣的是，我们发现移植前CD 28 + CD 8 +TEMRA细胞频率升高与贝拉西普治疗的排斥反应相关，而与他克莫司治疗无关。进一步的分析表明，在移植后，CD 28 + CD 8 +TEMRA细胞迅速失去CD 28表达，这些动物继续排斥，同种异体移植物浸润主要是CD 28-。这些数据表明，CD 28+记忆T细胞可能对贝拉西普具有抗性，能够进一步分化，包括CD 28表达的丧失，同时维持效应子功能。CD 28+记忆T细胞的独特信号传导需求为靶向治疗的开发提供了机会，靶向治疗可能与贝拉西普协同作用，以防止共刺激非依赖性排斥反应。
Recently newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28-CD80/86 specific reagent is associated with superior patient survival and graft function than traditional therapy but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely employed. To that end we designed a study in a non-human primate kidney transplant model where animals were treated with either a belatacept- or a tacrolimus-based immunosuppressive regimen. Interestingly we found that elevated pre-transplant frequencies of CD28+CD8+TEMRA cells are associated with rejection on belatacept but not tacrolimus treatment. Further analysis showed that the CD28+CD8+TEMRA cells rapidly lose CD28 expression after transplant in those animals that go on to reject with the allograft infiltrate being predominantly CD28−. These data suggest that CD28+ memory T cells may be resistant to belatacept, capable of further differentiation including loss of CD28 expression while maintaining effector function. The unique signaling requirements of CD28+ memory T cells provide opportunities for the development of targeted therapies, which may synergize with belatacept to prevent costimulation independent rejection.
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DOI：
10.1111/ajt.13613
发表时间：
2016-04
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Espinosa J;Herr F;Tharp G;Bosinger S;Song M;Farris AB 3rd;George R;Cheeseman J;Stempora L;Townsend R;Durrbach A;Kirk AD
通讯作者：
Kirk AD
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
发表时间：
2012-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Kitchens WH;Haridas D;Wagener ME;Song M;Kirk AD;Larsen CP;Ford ML
通讯作者：
Ford ML
影响因子：
15.9
作者：
Badell, Idelberto R.;Russell, Maria C.;Larsen, Christian P.
通讯作者：
Larsen, Christian P.
DOI：
10.1073/pnas.94.16.8789
发表时间：
1997-08-05
影响因子：
11.1
作者：
Kirk, AD;Harlan, DM;Knechtle, SJ
通讯作者：
Knechtle, SJ
影响因子：
8.8
作者：
Lamb, K. E.;Lodhi, S.;Meier-Kriesche, H. -U
通讯作者：
Meier-Kriesche, H. -U