Efficacy and safety of anti-CD19 CAR-T in a mouse model of IgG4-related disease

被引：2

作者：

Sun, Yeting ^{[1
,2
]}

Huang, Sicheng ^{[1
,2
]}

Zhang, Bo ^{[3
]}

Peng, Yu ^{[4
]}

Lu, Hui ^{[5
]}

Jia, Yimeng ^{[1
,2
]}

Sun, Ruijie ^{[1
,2
]}

Zhang, Fenghua ^{[6
]}

Zhou, Jiaxin ^{[1
,2
]}

Peng, Linyi ^{[1
,2
]}

Li, Mengtao ^{[1
,2
]}

Zhang, Wen ^{[1
,2
]}

Fei, Yunyun ^{[1
,7
]}

机构：

[1] Peking Union Med Coll & Chinese Acad Med Sci, Dept Rheumatol & Clin Immunol, Natl Clin Res Ctr Dermatol & Immunol Dis NCRC DID, Dept Hlth Management,Minist Sci & Technol,State Ke, Beijing, Peoples R China

[2] Natl Clin Res Ctr Dermatol & Immunol Dis NCRC DID, Minist Educ Key Lab, Beijing, Peoples R China

[3] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, State Key Lab Complex Severe & Rare Dis, Beijing 100730, Peoples R China

[4] Zhejiang Univ, Dept Rheumatol, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China

[5] Capital Med Univ, Beijing Chaoyang Hosp, Beijing, Peoples R China

[6] Second Hosp Harbin, Harbin, Peoples R China

[7] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Peking Union Med Coll, Dept Hlth Med, Beijing, Peoples R China

来源：

INTERNATIONAL IMMUNOPHARMACOLOGY | 2025年 / 145卷

基金：

北京市自然科学基金; 中国国家自然科学基金;

关键词：

IgG4-related disease; Chimeric antigen receptor T cell; B cell; Fibrosis; Infection; CHIMERIC ANTIGEN RECEPTOR; ANTITUMOR-ACTIVITY; CELLS; CD19; ACTIVATION; THERAPY; ESCAPE; MICE;

D O I：

10.1016/j.intimp.2024.113779

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Dysregulated B-cell activation plays pivotal roles in IgG4-related disease (IgG4-RD), which makes B-cell depletion a potential strategy for IgG4-RD treatment. In this study, we aimed to investigate the feasibility of applying anti-CD19 chimeric antigen receptor T(CAR-T) cell therapy to IgG4-RD treatment in a mouse disease model based on LatY136F knock-in (Lat) mice. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into Lat mice. Next, we assessed the safety of CAR-T infusion by evaluating the risk of cytokine release syndrome (CRS) and the antiviral capabilities in a mouse influenza infection model. Finally, we performed human anti-CD19 CAR-T manufacturing from IgG4-RD patients and evaluated its activation level and functional effects in vitro. Compared with 1D3 antibody treatment, the adoptive transfer of anti-CD19 CAR-T cells with CD28 costimulatory motif showed comparable B-cell-depletion effect in Lat mice. Furthermore, the transfer of syngeneic anti-CD19 CAR-T cells also decreased the percentage of plasma cells as well as IL-4 secreting Th cells, therefore attenuating the inflammation and fibrosis condition. CAR-T cells with CD28 costimulatory motif showed better therapeutic efficiency without the incidence of serious CRS events or increasing the risk infection. In addition, we validated the feasibility of human CAR-T preparation in vitro from IgG4-RD patients. Taken together, these results show that anti-CD19 CAR-T therapy was effective in the treatment of a murine model of IgG4-RD, indicating its potential for clinical use in patients.

引用

页数：13

共 56 条

[1] Induction of T helper type 2 immunity by a point mutation in the LAT adaptor [J].