Checkpoint Blockade Toxicity and Immune Homeostasis in the Gastrointestinal Tract.
Checkpoint Blockade Toxicity and Immune Homeostasis in the Gastrointestinal Tract.
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DOI：
10.3389/fimmu.2017.01547
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发表时间：
2017
影响因子：
7.3
通讯作者：
Dougan M
中科院分区：
文献类型：
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作者：
Dougan M
针对调节性免疫“检查点”受体CTLA-4、PD-1和PD-L1的单抗现在是包括黑色素瘤、肺癌和肾癌在内的各种恶性肿瘤的标准治疗方法。虽然在许多患者中有效，并能够在一些患者中诱导治愈，但针对这些调节途径已导致一类新的免疫相关不良事件。在许多方面，这些免疫毒性类似于特发性自身免疫性疾病，如炎症性肠病、自身免疫性肝炎、类风湿性关节炎和白癜风。了解这些免疫毒性的发病机制不仅对接受检查点封锁的患者的护理有意义，而且可能为自身免疫性疾病提供关键的见解。胃肠道(GI)黏膜可以说是体内最复杂的屏障，拥有各种各样的共生微生物群，并不断受到摄入的外来蛋白的挑战，这两种蛋白都必须被耐受。同时，胃肠道粘膜必须抵御病原微生物，同时保持足够的通透性来吸收营养。由于这些原因，调节细胞和受体很可能在维持肠道屏障和胃肠道毒性方面发挥核心作用，结肠炎和肝炎确实是CTLA-4阻断最常见的副作用之一，而PD-1和PD-L1的副作用较少。大剂量皮质类固醇通常对检查点结肠炎和肝炎都有效，尽管一小部分患者需要额外的免疫抑制，如英夫利昔单抗。及时认识和治疗这些毒性对于预防更严重的并发症至关重要。
Monoclonal antibodies targeting the regulatory immune “checkpoint” receptors CTLA-4, PD-1, and PD-L1 are now standard therapy for diverse malignancies including melanoma, lung cancer, and renal cell carcinoma. Although effective in many patients and able to induce cures in some, targeting these regulatory pathways has led to a new class of immune-related adverse events. In many respects, these immune toxicities resemble idiopathic autoimmune diseases, such as inflammatory bowel disease, autoimmune hepatitis, rheumatoid arthritis, and vitiligo. Understanding the pathogenesis of these immune toxicities will have implications not only for care of patients receiving checkpoint blockade but may also provide critical insights into autoimmune disease. The gastrointestinal (GI) mucosa is arguably the most complex barrier in the body, host to a diverse commensal microflora and constantly challenged by ingested foreign proteins both of which must be tolerated. At the same time, the GI mucosa must defend against pathogenic microorganisms while maintaining sufficient permeability to absorb nutrients. For these reasons, regulatory cells and receptors are likely to play a central role in maintaining the gut barrier and GI toxicities, such as colitis and hepatitis are indeed among the most common side effects of CTLA-4 blockade and to a lesser extent blockade of PD-1 and PD-L1. High-dose corticosteroids are typically effective for management of both checkpoint colitis and hepatitis, although a fraction of patients will require additional immune suppression such as infliximab. Prompt recognition and treatment of these toxicities is essential to prevent more serious complications.