Peng Jhan-Jie, Ding Jing-Ya, Xu Yingxi, Shih Han-Po, Lin You-Ning, Wu Tsai-Yi, Lo Yu-Fang, Lo Chia-Chi, Yeh Chu-Fu, Kuo Chen-Yen, Tu Kun-Hua, Wang Shang-Yu, Lei Wei-Te, Wu Ting-Shu, Lin Huang-Shen, Lee Chen-Hsiang, Huang Wen-Chi, Chen Yi-Chun, Liu Yuag-Meng, Shi Zhi-Yuan, Chang Ya-Ting, Syue Ling-Shan, Chen Po-Lin, Teh Soon-Hian, Chou Chia-Huei, Ho Mao-Wang, Chi Chih-Yu, Ho Ping-Chih, Ku Cheng-Lung
Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan.
Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
Sci Immunol. 2025 May 9;10(107):eadm8186. doi: 10.1126/sciimmunol.adm8186.
Neutralizing anti-interferon-γ (IFN-γ) autoantibodies (nAIGAs) impair IFN-γ-mediated immunity, predisposing patients with nAIGAs to infection by nontuberculous mycobacteria, , and other intracellular pathogens. Current clinical management relies on continuous antimicrobial therapy, with no treatment offering sustained benefits. Here, we developed human chimeric autoantibody receptor (CAAR) T cells targeting autoreactive B cells expressing nAIGA B cell receptors (BCRs) using an IFN-γ receptor-irresponsive IFN-γ variant as bait. By exploiting a mouse model of nAIGA BCR-expressing B cell leukemia, we found that IFN-γ CAAR T cells lack off-target toxicity, including IFN-γ receptor cross-reactive toxicity and Fc-redirected toxicity. IFN-γ CAAR T cells substantially reduced circulating AIGAs secreted from target cells in vivo. Further, IFN-γ CAAR T cells effectively eliminated autoreactive B cells in ex vivo cultures of peripheral blood mononuclear cells from patients with nAIGAs. Together, these results demonstrate that IFN-γ CAAR T cells may be a promising strategy to ameliorate nAIGA-associated infections by eliminating autoreactive B cells.
中和抗干扰素-γ（IFN-γ）自身抗体（nAIGAs）会损害IFN-γ介导的免疫，使nAIGAs患者易受非结核分枝杆菌及其他细胞内病原体感染。目前的临床管理依赖持续的抗菌治疗，尚无治疗方法能带来持续益处。在此，我们利用对IFN-γ无反应的IFN-γ变体作为诱饵，开发了靶向表达nAIGA B细胞受体（BCRs）的自身反应性B细胞的人嵌合自身抗体受体（CAAR）T细胞。通过利用表达nAIGA BCR的B细胞白血病小鼠模型，我们发现IFN-γ CAAR T细胞缺乏脱靶毒性，包括IFN-γ受体交叉反应毒性和Fc重定向毒性。IFN-γ CAAR T细胞在体内显著减少了靶细胞分泌的循环AIGAs。此外，IFN-γ CAAR T细胞在nAIGAs患者外周血单个核细胞的体外培养中有效消除了自身反应性B细胞。总之，这些结果表明，IFN-γ CAAR T细胞可能是一种通过消除自身反应性B细胞来改善nAIGA相关感染的有前景的策略。
