Thymic and Lymphoid Changes and Serum Immunoglobulin Abnormalities in Mice Receiving Cyclosporine

The authors recently demonstrated that cyclosporine (CsA) enhanced the development of murine thymic lymphomas by its tumor promoter-like action. To clarify the underlying mechanism, they investigated the morphologic alterations in the thymus and other lymphoid tissues and the serum immunoglobulin abnormalities in mice receiving CsA. Feeding male Swiss Webster mice with diets containing 0.015% and 0.027% CsA for 1, 2, 4, and 8 weeks led to a marked reduction of the thymic medulla. Thymocytes remaining after CsA treatment were completely destroyed by a single injection of cortisone acetate (8 mg/mice), and cortisone-resistant cells were markedly decreased. Immunoperoxidase staining using anti-keratin antibodies showed a decrease in the number of keratin-positive cells, presumably epithelial cells, in the thymus of CsA-treated mice. These changes were completely reversible within 4 weeks after withdrawing CsA from the diet. The lymph nodes and the gut-associated lymphoid tissues of CsA-treated mice showed blurring of the germinal centers, diminished Thy-1-positive lymphocytes, and proliferation of lymphocytes carrying IgG, IgM, and IgA on their surface. Similar changes were observed in the spleens of CsA-treated mice. There was a slight increase in serum IgG, a twofold increase in serum IgM, and a six- to tenfold increase in serum IgA. The results suggest that CsA interferes with the functions of both T and B lymphocytes in vivo and that disturbance of T-cell maturation in the thymus may be the mechanism by which CsA promotes the induction of thymic lymphomas in mice.