Senant Marie, Giusti Delphine, Weiss Laurence, Dragon-Durey Marie-Agnès
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Service d'immunologie biologique, hôpital européen Georges-Pompidou, Assistance publique-hôpitaux de Paris.
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Service d'immunologie clinique, hôpital européen Georges-Pompidou, Assistance publique-hôpitaux de Paris.
Bull Cancer. 2016 Nov;103 Suppl 1:S175-S185. doi: 10.1016/S0007-4551(16)30376-9.
AUTOIMMUNITY AND MANAGEMENT OF THE IMMUNE-RELATED ADVERSE EFFECTS OF THE IMMUNE CHECKPOINT INHIBITORS: The immune checkpoint molecules such as CTLA-4 and PD-1 are involved in the tolerance mechanisms preventing the immune system to react against the self-antigens. When these receptors expressed on the lymphocyte membrane, bind to their ligands, they induce a negative signal to the cell which becomes unable to be completely activated in the presence of its antigen. In a context of tumor, the infiltrating T cells are frequently exhausted due to the expression of CTLA-4 and PD-1 ligands by the microenvironment impairing the antitumoral immunity. The use of antagonistic antibodies targeting these receptors or their ligands (called checkpoint inhibitors) aims to block their interaction unbalancing the negative regulation of the antitumoral lymphocytes. However, this effect affects all lymphocytes and may also disrupt the negative regulation of the peripheral autoreactive lymphocytes. Thus, a significant proportion of patients treated by these molecules develop immune-related symptoms affecting different tissues and organs due to lymphocyte activation. These symptoms are called immune-related adverse events (irAEs). This article aims to summarize the scientific data demonstrating the implication of these molecules in the tolerance mechanisms and in the autoimmune diseases. It also reports on the IrAEs observed in treated patients and gives an outline of guidelines to monitor and manage these patients.
免疫检查点分子如CTLA-4和PD-1参与了防止免疫系统对自身抗原产生反应的耐受机制。当这些在淋巴细胞膜上表达的受体与其配体结合时，它们会向细胞发出负信号，导致细胞在存在抗原的情况下无法被完全激活。在肿瘤环境中，由于微环境中CTLA-4和PD-1配体的表达损害了抗肿瘤免疫，浸润的T细胞经常处于耗竭状态。使用针对这些受体或其配体的拮抗抗体（称为检查点抑制剂）旨在阻断它们的相互作用，从而打破对抗肿瘤淋巴细胞的负调节。然而，这种作用会影响所有淋巴细胞，也可能破坏外周自身反应性淋巴细胞的负调节。因此，相当一部分接受这些分子治疗的患者会因淋巴细胞激活而出现影响不同组织和器官的免疫相关症状。这些症状被称为免疫相关不良事件（irAEs）。本文旨在总结科学数据，证明这些分子在耐受机制和自身免疫性疾病中的作用。它还报告了在接受治疗的患者中观察到的irAEs，并概述了监测和管理这些患者的指南。
