Expression of Immunoregulatory Molecules by Thyrocytes Protects Nonobese Diabetic-H2h4 Mice from Developing Autoimmune Thyroiditis

Abstract

One approach to prevent tissue destruction by autoimmune attack in organ-specific autoimmune diseases is to protect the target tissue from autoimmune reaction, regardless of its persistent activity. To provide proof-of-principle for the feasibility of this approach, the immunoregulatory molecules, TNF-related apoptosis-inducing ligand (TRAIL) and indoleamine 2, 3-dioxygenase, were expressed in the thyroid glands using adenovirus vector in nonobese diabetic-H2(h4) mice that spontaneously develop thyroiditis. Mice were anesthetized, and the thyroid glands were exposed by neck dissection, followed by in situ infection with adenovirus vector (5 x 10(10) particles per mouse) twice or thrice, starting 1 d or 4 wk before mice were supplied with sodium iodine (NaI) water. After 8 wk NaI provision, the extent of thyroiditis, serum titers of antithyroglobulin antibodies, and cytokine expression in the spleen were examined. In situ infection of adenovirus expressing TRAIL or indoleamine 2, 3-dioxygenase, but not green fluorescent protein, significantly suppressed thyroiditis scores. However, antithyroglobulin antibody titers and expression levels of cytokines (interferon-gamma and IL-4) in the spleen remained unaltered. Importantly, adenovirus infection 4 wk after NaI provision was also effective at suppressing thyroiditis. The suppressive effect of TRAIL appears to be mediated at least partly by accumulation of CD4(+)Foxp3(+) regulatory T cells into the thyroid glands. Thus, localized expression of immunoregulatory molecules efficiently protected the thyroid glands from autoimmune attack without changing the systemic autoimmunity in nonobese diabetic-H2(h4) mice. This kind of immunological intervention, although it does not suppress autoimmune reactivity, may have a potential for treating organ-specific autoimmune diseases.

Iodine content of thyroglobulin in NOD.H2h4 mice developing iodine-accelerated autoimmune thyroiditis

“…38 Iodine may also directly impair the function of regulatory T cells that have been known to contribute to ISAT resistance in NOD.H2 h4 mice. [39][40][41] Future research efforts in this area may yield new insights into the pathogenesis of thyroiditis. …”

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

“…Moreover, a beneficial effect has been shown after administration of a subset of myeloid cells that increase IDO synthesis, leading to expansion of regulatory T cells and correction of hyperglycemia in a mouse model of type 1 diabetes (36). Similarly, NOD-H2 h4 mice developed an attenuated form of thyroiditis when injected with an adenovirus expressing IDO directly into the thyroid gland one day before and four weeks after the beginning of iodine supplementation in the drinking water (37). But contrasting results have been obtained in other diseases.…”

Biochemical and immunological markers of autoimmune thyroiditis

“…[6]. Причём, TRAIL опосредует как апоптоз тиреоцитов, так и цитотоксических аутореактивных лимфоцитов [23]. TNF-a является гомологом FasL, что свидетельствует о его высокой апоптогенной активности [24].…”