Suppression of autoimmune thyroid disease by FK 506: influence on thyroid-infiltrating cells, adhesion molecule expression and anti-thyroglobulin antibody production

Abstract

Autoimmune thyroid disease was induced in female PVG/c rats by neonatal thymectomy, followed by sublethal, whole body x-irradiation. Disease development, assessed by histological evidence of lymphocytic thyroiditis and circulating levels of anti-thyroglobulin antibodies, was reduced significantly by a 3-week course of FK 506 (0.5 or 1.5 mg/kg per day) commencing after the detection of autoantibody production. Thyroid-infiltrating mononuclear cells (MNC) in untreated rats stained predominantly for CD4+ and MHC class II antigen which was expressed widely on dendritic cells. Fewer infiltrating cells expressed TCR alpha/beta, CD5, CD8 or LFA-1 beta. Intercellular adhesion molecule-1 (ICAM-1) was observed on MNC, vascular endothelial cells and a minority of residual thyroid epithelial cells. FK 506 administration reduced markedly the incidence of infiltrating TCR alpha/beta +, CD5+, CD4+, CD8+, and LFA-1 beta + cells and the expression both of MHC class II antigens and ICAM-1 on MNC, endothelial cells and thyrocytes. Compared with normal PVG/c rats, there were reduced incidences of CD4+ CD8- and CD4- CD8+ lymphocytes and an elevation in the CD4+/CD8+ cell ratio in the spleens of animals with autoimmune thyroiditis. These changes were partially reversed by FK 506. Systemic drug levels estimated by enzyme immunosorbent assay were in excess of those known to blockade cytokine production by CD4+ T lymphocytes in vitro and some evidence of minor renal dysfunction was observed. The results are consistent with a therapeutic effect of FK 506 mediated via interference with CD4+ T lymphocyte function and adhesion molecule-dependent cytotoxic effector mechanisms.