Pituitary Expression of CTLA-4 Mediates Hypophysitis Secondary to Administration of CTLA-4 Blocking Antibody
Pituitary Expression of CTLA-4 Mediates Hypophysitis Secondary to Administration of CTLA-4 Blocking Antibody
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DOI：
10.1126/scitranslmed.3008002
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发表时间：
2014-04-02
影响因子：
17.1
通讯作者：
Caturegli, Patrizio
中科院分区：
文献类型：
--
作者：
Iwama, Shintaro;De Remigis, Alessandra;Caturegli, Patrizio
垂体炎是一种病因不明（原发性）或可识别（继发性）的垂体慢性炎症，例如在癌症免疫治疗中使用易普利姆玛。伊匹单抗阻断T细胞抑制分子CTLA-4（细胞毒性T淋巴细胞抗原-4），通过未知机制在约4%的患者中诱导垂体炎。我们首先通过向SJL/J或C57 BL/6 J小鼠重复注射CTLA-4阻断抗体建立了继发性垂体炎模型，并显示它们发展了垂体的淋巴细胞浸润和循环垂体抗体。接下来，我们评估了20例晚期黑色素瘤或前列腺癌患者（7例临床诊断为垂体炎）在伊匹单抗给药前后垂体抗体的患病率。在7例垂体炎患者中出现了基线阴性的peptide抗体，但在13例无垂体炎患者中未出现;这些抗体主要识别促甲状腺激素、促卵泡激素和促肾上腺皮质激素分泌细胞。然后我们假设，注射的CTLA-4抗体如果与垂体内分泌细胞上“异位”表达的CTLA-4抗原结合，可能会引起垂体毒性。事实上，前列腺在RNA和蛋白质水平上都表达CTLA-4，特别是在催乳素和促甲状腺素分泌细胞的亚群中。值得注意的是，这些细胞成为补体激活的位点，其特征是C3 d和C4d组分的沉积以及类似于II型超敏反应中所见的炎症级联反应。总之，该研究提供了一种机制来解释在接受伊匹单抗的患者中观察到的垂体毒性，并强调了测量垂体抗体在这种继发性垂体炎中的效用。
Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of patients through unknown mechanisms. We first established a model of secondary hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or C57BL/6J mice, and showed that they developed lymphocytic infiltration of the pituitary gland and circulating pituitary antibodies. We next assessed the prevalence of pituitary antibodies in a cohort of 20 patients with advanced melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before and after ipilimumab administration. Pituitary antibodies, negative at baseline, developed in the 7 patients with hypophysitis but not in the 13 without it; these antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone-, and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4 antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed "ectopically" on pituitary endocrine cells. Pituitary glands indeed expressed CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin-and thyrotropin-secreting cells. Notably, these cells became the site of complement activation, featuring deposition of C3d and C4d components and an inflammatory cascade akin to that seen in type II hypersensitivity. In summary, the study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis.