Exacerbation of Autoimmune Thyroiditis by CTLA-4 blockade: a role for IFNγ-induced indoleamine 2, 3-dioxygenase.

Exacerbation of Autoimmune Thyroiditis by CTLA-4 blockade: a role for IFNγ-induced indoleamine 2, 3-dioxygenase.:

Exacerbation of Autoimmune Thyroiditis by CTLA-4 blockade: a role for IFNγ-induced indoleamine 2, 3-dioxygenase.

Thyroid. 2016 Jun 13;

Authors: Sharma R, Di Dalmazi G, Caturegli P

Abstract
BACKGROUND: 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-H2h4 mouse, a model that develops thyroiditis at very high incidence after addition of iodine to the drinking water.
METHODS: NOD-H2h4 mice were started on drinking water supplemented with 0.05% sodium iodide when 8 weeks old, and then injected with either a hamster monoclonal antibody against mouse CTLA-4, or 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 thyroids and in isolated antigen-presenting cells after stimulation with IFNγ. The study also analyzed IDO expression in 4 autopsy cases of metastatic melanoma that had received treatment with a CTLA-4 blocking antibody, and 6 surgical pathology Hashimoto thyroiditis controls.
RESULTS: 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 IL-2, IFNγ,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.
CONCLUSIONS: This study shows that CTLA-4 blockade exacerbates the iodine-accelerated form of thyroiditis typical of the NOD.H2h4 mouse. The study could also have implications for cancer patients who develop thyroiditis as an immune-related adverse event after CTLA-4 blockade.

PMID: 27296629 [PubMed - as supplied by publisher]

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