Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor
Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor
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DOI：
10.1172/jci82771
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发表时间：
2016-04-01
影响因子：
15.9
通讯作者：
Levings, Megan K.
中科院分区：
文献类型：
--
作者：
MacDonald, Katherine G.;Hoeppli, Romy E.;Levings, Megan K.
调节性T细胞（Tregs）过继免疫治疗是治疗同种异体移植排斥和移植物抗宿主病（GVHD）的一种很有前景的治疗方法。新出现的数据表明，与多克隆treg相比，疾病相关抗原特异性treg可能具有许多优势，例如需要更少的细胞和降低非特异性免疫抑制的风险。目前产生同种异体抗原特异性treg的方法依赖于同种异体抗原呈递细胞的扩增，这需要接触供体和受体细胞以及多次MHC错配。嵌合抗原受体（CARs）成功地用于产生抗原特异性效应T细胞，这表明类似的方法可以用于产生异体抗原特异性treg。在这里，我们描述了hla - a2特异性CAR （A2-CAR）的创建及其在异体抗原特异性人类treg的产生中的应用。在体外，表达a2 - car的treg在a2 - car介导的刺激之前、期间和之后都保持了预期的表型和抑制功能。在小鼠模型中，表达人类a2 -CAR的Tregs在预防HLA-A2(+) T细胞引起的异种GVHD方面优于表达不相关CAR的Tregs。总之，我们的研究结果表明，使用CAR技术产生有效、功能和稳定的异体抗原特异性人类treg显著提高了它们在移植中的治疗潜力，并为使用这种方法制造抗原特异性treg治疗多种疾病奠定了基础。
Adoptive immunotherapy with regulatory T cells (Tregs) is a promising treatment for allograft rejection and graft-versus-host disease (GVHD). Emerging data indicate that, compared with polyclonal Tregs, disease-relevant antigen-specific Tregs may have numerous advantages, such as a need for fewer cells and reduced risk of nonspecific immune suppression. Current methods to generate alloantigen-specific Tregs rely on expansion with allogeneic antigen-presenting cells, which requires access to donor and recipient cells and multiple MHC mismatches. The successful use of chimeric antigen receptors (CARs) for the generation of antigen-specific effector T cells suggests that a similar approach could be used to generate alloantigen-specific Tregs. Here, we have described the creation of an HLA-A2-specific CAR (A2-CAR) and its application in the generation of alloantigen-specific human Tregs. In vitro, A2-CAR-expressing Tregs maintained their expected phenotype and suppressive function before, during, and after A2-CAR-mediated stimulation. In mouse models, human A2-CAR-expressing Tregs were superior to Tregs expressing an irrelevant CAR at preventing xenogeneic GVHD caused by HLA-A2(+) T cells. Together, our results demonstrate that use of CAR technology to generate potent, functional, and stable alloantigen-specific human Tregs markedly enhances their therapeutic potential in transplantation and sets the stage for using this approach for making antigen-specific Tregs for therapy of multiple diseases.