Role of TGF beta in development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice

Nearly 100% of NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (S AT) and produce anti-mouse thyroglobulin autoantibodies when they receive 0 .05% NaI in their drinking water beginning at 8 wk of age. Our previous stu dies showed that TGF beta1 mRNA was constitutively expressed in thyroids an d spleens of normal NOD.H-2h4 mice but not other strains of mice. To determ ine whether TGF beta might have a role in SAT, mice were given anti-TGF bet a mAb at various times during development of SAT. Anti-TGF beta markedly in hibited development of SAT and production of anti-mouse thyroglobulin IgG1 autoantibodies. Anti-TGF beta was most effective in inhibiting SAT when giv en during the time thyroid lesions were developing, i.e., starting 4 wk aft er administration of NaI water. The active form of the TGF beta1 protein wa s present in thyroids of mice with SAT but not in normal NOD.H-2h4 thyroids . However, thyrocytes of normal NOD.H-2h4 thyroids did express latent TGF b eta1. TGF beta1 protein expression in the thyroid correlated with SAT sever ity scores, and administration of anti-TGF beta inhibited TGF beta1 protein expression in both the thyroid and spleen. TGF beta1 was produced primaril y by inflammatory cells and was primarily localized in areas of the thyroid containing clusters of CD4(+) T and B cells. Depletion of CD8(+) T cells h ad no effect on TGF beta1 protein expression. Activation of splenic T cells was apparently not inhibited by anti-TGF beta, because up-regulation of mR NA for cytokines and other T cell activation markers was similar for contro l and anti-TGF beta -treated mice. TGF beta1 may function by promoting migr ation to, or retention of, inflammatory cells in the thyroid.