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American Journal of Pathology, Vol 152, 1347-1358, Copyright © 1998 by American Society for Investigative Pathology
REGULAR ARTICLES |
H Braley-Mullen, GC Sharp, H Tang, K Chen, M Kyriakos and JT Bickel
Department of Internal Medicine, University of Missouri-Columbia School of Medicine, 65212, USA. helen_mullen@muccmail.missouri.edu
Granulomatous inflammatory lesions are a major histopathological feature of a wide spectrum of human infectious and autoimmune diseases. Experimental autoimmune thyroiditis (EAT) with granulomatous histopathological features can be induced by mouse thyroglobulin (MTg)- sensitized spleen cells activated in vitro with MTg and anti- interleukin-2 receptor (anti-IL-2R), anti-IL-2, or anti-interferon- gamma (anti-IFN-gamma) monoclonal antibody (MAb). These studies suggested that IFN-gamma-producing T cells requiring IL-2 for growth may negatively regulate activation of granulomatous EAT effector cells. As IL-12 promotes activation of IFN-gamma-producing Th1 cells, the present study was undertaken to determine the role of IL-12 in activation of effector cells for granulomatous EAT. MTg-sensitized cells activated in vitro with MTg, anti-IL2R MAb, and IL-12 induced severe, destructive granulomatous thyroiditis with neutrophil inflammation, fibrin deposition, and necrosis. Many glands ultimately underwent atrophy and became fibrotic; some also showed fibrinoid necrosis and a mixed inflammatory cell infiltration of blood vessel walls indicative of a necrotizing vasculitis. Induction of severe granulomatous EAT by IL-12 required MTg in vitro and was unrelated to the IL-12-induced increase in IFN-gamma production. IL-12 markedly increased IFN-gamma production but did not induce a shift to a Th1- dominant phenotype, as other Th1 and Th2 cytokines were generally unaffected and both Th1 and Th2 cytokines were expressed in recipient thyroids. Addition of IL-12 or neutralization by anti-IL-12 at various times indicated that IL-12 exerted its primary effects in the final 24 hours of the 72-hour culture and was not required in recipient mice. Cells cultured with anti-IL-12, MTg, and anti-IL2R MAb transferred mild lymphocytic EAT but little or no granulomatous EAT. Thus, IL-12 profoundly regulates the in vitro activation of effector cells that induce histologically distinct autoimmune inflammatory lesions in the thyroid.
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