Sharma Rajni, Di Dalmazi Giulia, Caturegli Patrizio
1 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland.
2 Department of Medicine, G. d'Annunzio University of Chieti , Cheti, Italy .
Thyroid. 2016 Aug;26(8):1117-24. doi: 10.1089/thy.2016.0092. Epub 2016 Jul 22.
Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a negative regulator of immune responses that suppresses the activity of effector T cells and contributes to the maintenance of self tolerance. When blocked therapeutically, CTLA-4 leads to an overall activation of T cells that has been exploited for cancer control, a control associated however with a variety of immune-related side effects such as autoimmune thyroiditis. To investigate the mechanism(s) underlying this form of thyroiditis, we used the NOD-H2(h4) mouse, a model that develops thyroiditis at very high incidence after addition of iodine to the drinking water.
NOD-H2(h4) mice were started on drinking water supplemented with 0.05% sodium iodide when 8 weeks old and then injected with a hamster monoclonal antibody against mouse CTLA-4, polyclonal hamster immunoglobulins, or phosphate buffered saline when 11 weeks old. One month later (15 weeks of age), mice were sacrificed to assess thyroiditis, general immune responses in blood and spleen, and expression of indoleamine 2, 3-dioxygenase (IDO) in the thyroid and in isolated antigen-presenting cells after stimulation with interferon gamma. The study also analyzed IDO expression in four autopsy cases of metastatic melanoma who had received treatment with a CTLA-4 blocking antibody, and six surgical pathology Hashimoto thyroiditis controls.
CTLA-4 blockade worsened autoimmune thyroiditis, as assessed by a greater incidence, a more aggressive mononuclear cell infiltration in thyroids, and higher thyroglobulin antibody levels when compared to the control groups. CTLA-4 blockade also expanded the proportion of splenic CD4+ effector T cells, as well as the production of interleukin (IL)-2, interferon gamma, IL-10, and IL-13 cytokines. Interestingly, CTLA-4 blockade induced a strong expression of IDO in mouse and human thyroid glands, an expression that could represent a counter-regulatory mechanism to protect against the inflammatory environment.
This study shows that CTLA-4 blockade exacerbates the iodine-accelerated form of thyroiditis typical of the NOD-H2(h4) mouse. The study could also have implications for cancer patients who develop thyroiditis as an immune-related adverse event after CTLA-4 blockade.
细胞毒性T淋巴细胞相关蛋白4（CTLA-4）是免疫反应的负调节因子，可抑制效应T细胞的活性并有助于维持自身耐受性。当通过治疗性阻断CTLA-4时，会导致T细胞的全面激活，这已被用于癌症控制，但这种控制与多种免疫相关的副作用有关，如自身免疫性甲状腺炎。为了研究这种形式的甲状腺炎的潜在机制，我们使用了NOD-H2（h4）小鼠，该模型在饮用水中添加碘后会以非常高的发病率发生甲状腺炎。
NOD-H2（h4）小鼠在8周龄时开始饮用补充有0.05%碘化钠的水，然后在11周龄时注射抗小鼠CTLA-4的仓鼠单克隆抗体、多克隆仓鼠免疫球蛋白或磷酸盐缓冲盐水。1个月后（15周龄），处死小鼠以评估甲状腺炎、血液和脾脏中的一般免疫反应，以及在用干扰素γ刺激后甲状腺和分离的抗原呈递细胞中吲哚胺2,3-双加氧酶（IDO）的表达。该研究还分析了4例接受CTLA-4阻断抗体治疗的转移性黑色素瘤尸检病例和6例手术病理桥本甲状腺炎对照中的IDO表达。
与对照组相比，通过更高的发病率、甲状腺中更具侵袭性的单核细胞浸润以及更高的甲状腺球蛋白抗体水平评估，CTLA-4阻断使自身免疫性甲状腺炎恶化。CTLA-4阻断还扩大了脾脏CD4+效应T细胞的比例，以及白细胞介素（IL）-2、干扰素γ、IL-10和IL-13细胞因子的产生。有趣的是，CTLA-4阻断在小鼠和人类甲状腺中诱导了IDO的强烈表达，这种表达可能代表一种对抗炎症环境的反调节机制。
本研究表明，CTLA-4阻断会加剧NOD-H2（h4）小鼠典型的碘加速型甲状腺炎。该研究也可能对CTLA-4阻断后发生甲状腺炎作为免疫相关不良事件的癌症患者有影响。
