In vitro elimination of autoreactive B cells from rheumatoid arthritis patients by universal chimeric antigen receptor T cells
In vitro elimination of autoreactive B cells from rheumatoid arthritis patients by universal chimeric antigen receptor T cells
复制标题
通用嵌合抗原受体 T 细胞体外消除类风湿关节炎患者自身反应性 B 细胞
DOI：
10.1136/annrheumdis-2020-217844
复制
发表时间：
2020-09
影响因子：
27.4
通讯作者：
Xuan Zhang
中科院分区：
文献类型：
--
作者：
Bo Zhang;Yan Wang;Yeshuang Yuan;Jiaqi Sun;Lulu Liu;Dan Huang;Jin Hu;Min Wang;Shengjie Li;Wei Song;Hua Chen;Demin Zhou;Xuan Zhang
自身反应性B细胞在类风湿关节炎（RA）的发病机制中起着至关重要的作用，使用抗体（如利妥昔单抗）的B细胞消耗疗法已被认为是治疗类风湿关节炎的有效方法。然而，利妥昔单抗的短暂B细胞消耗与免疫系统的整体抑制相关的重大安全性挑战相关，因此增加了感染和癌症发展的风险。为了解决与RA治疗相关的选择性和持久性问题，我们开发了一种定制的治疗策略，使用通用抗异硫氰酸荧光素（FITC）嵌合抗原受体T细胞（CAR-T细胞）结合FITC标记的抗原肽表位来消除RA中识别这些抗原的自身反应性B细胞亚群。方法在概念验证研究中，选择了来自瓜氨酸化自身抗原的四个瓜氨酸化肽表位，即瓜氨酸化vimentin、瓜氨酸化II型胶原、瓜氨酸化纤维蛋白原和tenascin-C，以及环瓜氨酸肽-1作为靶向自身反应性B细胞的配体；我们构建了表达固定抗fitc CAR的工程化T细胞，并将其作为通用的CAR-T细胞系统，通过识别上述fitc标记的自身抗原肽表位，特异性地消除这些蛋白特异性的自身反应性B细胞。结果表明，抗fitc CAR-T细胞可以特异性重定向，并通过识别相应的fitc标记的瓜氨酸肽表位，杀死由抗原肽免疫产生的杂交瘤细胞和RA患者的自身反应性B细胞亚群。此外，CAR-T细胞的细胞毒性依赖于肽的存在，并以剂量依赖的方式发生。结论：本文描述的方法为精确定制治疗RA的方法提供了方向，并可能应用于其他系统性自身免疫性疾病。
Objectives Autoreactive B cells play a crucial role in the pathogenesis of rheumatoid arthritis (RA), and B cell-depleting therapies using an antibodies, such as rituximab, have been suggested to be effective in RA treatment. However, transient B cell depletion with rituximab is associated with significant safety challenges related to global suppression of the immune system and thus increases the risks of infection and cancer development. To address selective and persistent issues associated with RA therapy, we developed a customised therapeutic strategy employing universal antifluorescein isothiocyanate (FITC) chimeric antigen receptor T cells (CAR-T cells) combined with FITC-labelled antigenic peptide epitopes to eliminate autoreactive B cell subsets recognising these antigens in RA. Methods For a proof-of-concept study, four citrullinated peptide epitopes derived from citrullinated autoantigens, namely, citrullinated vimentin, citrullinated type II collagen, citrullinated fibrinogen and tenascin-C, and a cyclocitrulline peptide-1 were selected as ligands for targeting autoreactive B cells; Engineered T cells expressing a fixed anti-FITC CAR were constructed and applied as a universal CAR-T cell system to specifically eliminate these protein-specific autoreactive B cells via recognition of the aforementioned FITC-labelled autoantigenic peptide epitopes. Results We demonstrated that anti-FITC CAR-T cells could be specifically redirected and kill hybridoma cells generated by immunisation with antigenic peptides, and autoreactive B cell subsets from RA patients via recognition of corresponding FITC-labelled citrullinated peptide epitopes. Additionally, the cytotoxicity of the CAR-T cells was dependent on the presence of the peptides and occurred in a dose-dependent manner. Conclusions The approach described here provides a direction for precise, customised approaches to treat RA and can likely be applied to other systemic autoimmune diseases.
登录
查看更多内容
滑膜组织对利妥昔单抗的反应：作用机理和反应生物标志物的鉴定。
影响因子：
27.4
作者：
Thurlings, R. M.;Vos, K.;Wijbrandts, C. A.;Zwinderman, A. H.;Gerlag, D. M.;Tak, P. P.
通讯作者：
Tak, P. P.
DOI：
10.1073/pnas.1524155113
发表时间：
2016-01-26
影响因子：
11.1
作者：
Rodgers, David T.;Mazagova, Magdalena;Young, Travis S.
通讯作者：
Young, Travis S.
影响因子：
--
作者：
Cantaert, Tineke;Teitsma, Christine;Baeten, Dominique
通讯作者：
Baeten, Dominique
影响因子：
27.4
作者：
Suwannalai, Parawee;Britsemmer, Karin;Trouw, L. A.
通讯作者：
Trouw, L. A.
影响因子：
11.2
作者：
Raedun Clarke;Matthieu Bauer;R. Bjordahl;Jeffrey Sasaki;Brian C. Groff;S. Gaidarova;Tom Tong Lee;Weijie Lan;M. Burrascano;Ramzey Abujarour;G. Bonello;Megan Robinson;Stewart Abbot;Scott Wolchko;Daniel Shoemaker;Bob Valamehr
通讯作者：
Raedun Clarke;Matthieu Bauer;R. Bjordahl;Jeffrey Sasaki;Brian C. Groff;S. Gaidarova;Tom Tong Lee;Weijie Lan;M. Burrascano;Ramzey Abujarour;G. Bonello;Megan Robinson;Stewart Abbot;Scott Wolchko;Daniel Shoemaker;Bob Valamehr