New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland.

Sixty to seventy percent of IFN-γ(-/-) NOD.H-2h4 mice given sodium iodide (NaI)-supplemented water develop a slow onset autoimmune thyroid disease, characterized by thyrocyte epithelial cell (TEC) hyperplasia and proliferation (H/P). TEC H/P develops much earlier in CD28(-/-) mice and nearly 100% (both sexes) have severe TEC H/P at 4 mo of age. Without NaI supplementation, 50% of 5- to 6-mo-old CD28(-/-)IFN-γ(-/-) mice develop severe TEC H/P, and 2-3 wk of NaI is sufficient for optimal development of severe TEC H/P. Mice with severe TEC H/P are hypothyroid, and normalization of serum thyroxine levels does not reduce TEC H/P. Activated CD4(+) T cells are sufficient to transfer TEC H/P to SCID recipients. Thyroids of mice with TEC H/P have infiltrating T cells and expanded numbers of proliferating thyrocytes that highly express CD40. CD40 facilitates, but is not required for, development of severe TEC H/P, as CD40(-/-)IFN-γ(-/-)CD28(-/-) mice develop severe TEC H/P. Accelerated development of TEC H/P in IFN-γ(-/-)CD28(-/-) mice is a result of reduced regulatory T cell (Treg) numbers, as CD28(-/-) mice have significantly fewer Tregs, and transfer of CD28(+) Tregs inhibits TEC H/P. Essentially all female IFN-γ(-/-)CD28(-/-) NOD.H-2h4 mice have substantial lymphocytic infiltration of salivary glands and reduced salivary flow by 6 mo of age, thereby providing an excellent new model of autoimmune exocrinopathy of the salivary gland. This is one of very few models where autoimmune thyroid disease and hypothyroidism develop in most mice by 4 mo of age. This model will be useful for studying the effects of hypothyroidism on multiple organ systems.

Agonistic anti-CD40 promotes early development and increases the incidence of severe thyroid epithelial cell hyperplasia (TEC H/P) in CD4-/- mice.

IFN-γ-/-NOD.H-2h4 mice develop thyroid epithelial cell hyperplasia (TEC H/P) characterised by abnormal proliferation of thyrocytes and infiltration of thyroids by CD4+ and CD8+ T cells, macrophages and dendritic cells. CD8+ T cells from mice with severe TEC H/P transfer similar lesions to SCID recipients, whereas CD4+ T cells transfer mild TEC H/P. CD4- and CD8- deficient IFN-γ-/-NOD.H-2h4 mice were generated to determine if CD4+ T cells were required for initial activation of the CD8+ T cells that transfer TEC H/P. After 6-8 months on NaI water, only 2 of 60 CD8-/- mice developed severe TEC H/P, whereas 31 of 101 CD4-/- mice developed severe TEC H/P and fibrosis comparable in severity to that of IFN-γ-/- mice. However, splenocytes from CD4-/- mice with severe TEC H/P did not effectively transfer severe TEC H/P to SCID recipients. When CD4-/- donors were given agonistic anti-CD40 mAb, most developed severe TEC H/P and their cells transferred severe TEC H/P to SCID recipients. These results indicate that agonistic anti-CD40 can provide an important signal for activation of autoreactive CD8+ T cells that transfer severe TEC H/P. Therefore, targeting or blocking CD40 could provide effective therapy for diseases involving hyperplasia and fibrosis mediated by CD8+ T cells.