Interestingly, the original authors also noted that addition of sodium iodide to the drinking water accelerated the incidence and severity of thyroiditis in the NOD-H2h4but not the parental NOD strain (8), an observation later confirmed and expanded by others (9,10). 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 activation with interferon gamma. The study also analyzed IDO expression in four autopsy cases of metastatic melanoma who experienced received treatment with a CTLA-4 blocking antibody, and six surgical pathology Hashimoto thyroiditis controls. Results:CTLA-4 blockade worsened autoimmune thyroiditis, as assessed by a greater incidence, Rabbit polyclonal to Synaptotagmin.SYT2 May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. 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 FPH2 (BRD-9424) 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 common of the NOD-H2h4mouse. The study could also have implications for malignancy patients who develop thyroiditis as an immune-related adverse event after CTLA-4 blockade. == Introduction == Autoimmune thyroiditishas been modeled in animals since the mid-1950s. For the first four decades, models were mainly based on immunizations with whole thyroid extracts (1) or thyroglobulin (2). Since the early 1990s, autoimmune thyroiditis has also been analyzed using mice that develop it spontaneously, the so-called NOD-H2h4model. The NOD-H2h4mouse was discovered serendipitously by Linda Wicker’s laboratory at Merck while studying the influence of the major histocompatibility complex around the NOD model FPH2 (BRD-9424) of type 1 diabetes (3). The authors noted that this congenic NOD-H2h4strain (Kk, Ak, E0, Db) lost the spontaneous development of diabetes common of the parental NOD strain (Kd, Ag7, E0, Db) but acquired thyroiditis, as assessed by the appearance of mononuclear cell infiltration in the thyroid gland and circulating thyroglobulin antibodies. It is now well established that thyroiditis in NOD-H2h4mice first emerges at about four months of age and becomes fully prevalent at 12 months (4,5). In contrast to the human counterpart (Hashimoto thyroiditis), in NOD-H2h4mice thyroperoxidase antibodies develop only later (6), thyroxine remains normal (7), and males are as equally affected as females (4,5). Interestingly, the original authors also noted that addition of sodium iodide to the drinking water accelerated the incidence and severity of thyroiditis in the NOD-H2h4but not the parental NOD strain (8), an observation later confirmed and expanded by others (9,10). More specifically, once iodine-rich water supplementation is started (typically carried out at two months of age), thyroiditis ensues within two weeks and becomes fully prevalent at about five months of age (5). This anticipation and worsening of thyroiditis by iodine has been the subject of numerous studies and hypotheses (4,5). One view is usually that incorporation of iodine in thyroglobulin renders this autoantigen more immunogenic, and thus more easily recognizable by autoreactive T cells. Another view is usually that iodine directly affects the thyrocytes by making them more susceptible to apoptosis via dysregulation of oxidative stress control mechanisms or by rendering them a better homing site for circulating effector T cells via upregulation of adhesion molecules (11). In addition to these thyroid-centered mechanisms, it has also been shown that iodine reduces the number and/or function of regulatory T cells (Tregs), potentially tipping the immunoregulatory balance toward autoimmunity. In fact, iodine feeding decreases the proportion of CD4+CD25+Foxp3+Tregsin the spleen (12,13) and thyroid glands (14) of NOD-H2h4mice. In addition, NOD-H2h4mice lacking the T cell FPH2 (BRD-9424) costimulatory molecule CD28 develop a more severe form of iodine-accelerated thyroiditis and have fewer Tregsin spleen and cervical lymph nodes (15). Similarly, Tregsdepletion by injection of an anti-CD25 antibody for four days prior to the iodine supplementation induced a more severe form of thyroiditis and higher thyroglobulin antibody titers (16). Overall, these studies emphasize the importance of Tregsand costimulatory signals in the pathogenesis of autoimmune thyroiditis, in keeping with the findings reported in other autoimmune conditions (17). In recent years, T-cell costimulatory signals have become the target of monoclonal antibody therapies in patients with a variety of cancers, firmly establishing.