Skin granuloma formation in mice immunosuppressed by cyclosporine

Granulomatous tissue reactions appear in athymic mouse skin, indicating that initiation of granuloma formation may be T-cell independent. To further evaluate the relationships between granuloma formation and T-cell function, we treated euthymic BALB/c mice with cyclosporine (Cs), a potent immunosuppressive drug, injected intramuscularly (150 mg/kg/day) 5 times a week. Hepatic granulomas were isolated from mice with schistosomiasis and transplanted into the skin of mice treated with Cs for 2 weeks. Cyclosporine injection was continued for 3 additional weeks. Blood levels of the drug increased during treatment (489 ng/ml at 2 weeks and 822 ng/ml at 5 weeks). Morphologically identical granulomas developed in both treated and untreated mice. Examination for T-cell functions showed that by the end of 2 weeks treatment, concanavalin A, phytohemagglutinin responses, and IL-2 activity were markedly depressed, and IL-2 receptor expression was not detected in either lymph nodes or spleen of the Cs-treated mice; however, after hepatic granuloma graft, T-cell functions in regional lymph nodes, but not in spleen, as well as peripheral blood eosinophilia were stimulated in Cs-treated mice. These data strongly suggest that intact T-cell activity is not essential for the initiation of granuloma formation. In addition, granuloma grafts appear to stimulate Cs-resistant T-cell activation locally, which amplifies and organizes the granulomatous response.