CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment.
CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment.
复制标题
CTLA-4 抗体-药物偶联物揭示了与调节性 T 细胞损伤相关的 B 淋巴细胞的自体破坏。
DOI：
10.1101/2023.03.01.530608
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Liu,Yang
中科院分区：
文献类型：
--
作者：
Muthana,MuslehM;Du,Xuexiang;Liu,Mingyue;Wang,Xu;Wu,Wei;Ai,Chunxia;Su,Lishan;Zheng,Pan;Liu,Yang
生殖细胞系CTLA-4缺乏引起严重的自身免疫性疾病，其特征在于Foxp 3 + T细胞调节异常、效应记忆T细胞的过度活化和可变形式的自身免疫性血细胞减少症，包括B细胞的逐渐丧失。接受抗CTLA-4/PD-1联合免疫治疗后发生严重免疫相关不良事件（irAE）的癌症患者外周B细胞也明显减少。B细胞丢失的免疫学基础仍然无法解释。在这里，我们通过使用与药物有效负载安坦辛（抗CTLA-4 ADC）缀合的抗人CTLA-4抗体伊匹单抗来探测人CTLA-4敲入小鼠中B细胞的下降。经抗CTLA-4 ADC处理的小鼠具有T细胞过度增殖及其分化成效应细胞，这导致B细胞耗竭。B细胞耗竭由CD 4和CD 8 T细胞介导，并且至少部分由抗TNF-α抗体拯救。这些数据揭示了T和B细胞之间的意外拮抗作用以及调节性T细胞在保存B细胞中的重要性。
Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here, we probe the decline of B cells in human CTLA-4 knock-in mice by using anti-human CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.