Inhibition of TGFbeta1 by anti-TGFbeta1 antibody or lisinopril reduces thyroid fibrosis in granulomatous experimental autoimmune thyroiditis.

In this study, a murine model of granulomatous experimental autoimmune thyroiditis (G-EAT) was used to determine the role of TGFbeta1 in fibrosis initiated by an autoimmune inflammatory response. The fibrotic process was evaluated by staining thyroid tissue for collagen, alpha-smooth muscle actin, TGFbeta1, and angiotensin-converting enzyme (ACE), and measuring serum thyroxine in mice given anti-TGFbeta1 or the ACE inhibitor lisinopril. The role of particular inflammatory cells in fibrosis was tested by depletion experiments, and the cytokine profile in thyroids was examined by RT-PCR. Neutralization of TGFbeta1 by anti-TGFbeta1 or lisinopril resulted in less collagen deposition and less accumulation of myofibroblasts, and levels of active TGFbeta1 and ACE were reduced in thyroids of treated mice compared with those of untreated controls. Other profibrotic molecules, such as platelet-derived growth factor, monocyte chemotactic protein-1, and IL-13, were also reduced in thyroids of anti-TGFbeta1- and lisinopril-treated mice compared with those of controls. Confocal microscopy showed that CD4(+) T cells and macrophages expressed TGFbeta1. Fibrosis was reduced by injection of anti-CD4 mAb on day 12, when G-EAT was very severe (4-5+). Together, these results suggest a critical role for TGFbeta1 in fibrosis initiated by autoimmune-induced inflammation. Autoreactive CD4(+) T cells may contribute to thyroid fibrosis through production of TGFbeta1. This G-EAT model provides a new model to study how fibrosis associated with autoimmune damage can be inhibited.