Cyclosporin A-induced autoimmune disease in mice.

The immunosuppressive drug cyclosporin A (CsA) disrupts the process of thymic ontogeny and repertoire selection in the alpha beta T cell population. Although treatment with this agent does not cause overt abnormalities in adult animals by itself, in lethally irradiated rats reconstituted with syngeneic bone marrow cells, CsA treatment results in an autoimmune syndrome. In this report, a modified protocol is described to obtain a similar, but distinctive, pathologic syndrome in mice. The key elements of this protocol are stringent elimination of mature T cells from the bone marrow cells used to reconstitute the irradiated recipients and the use of high doses of CsA over a long course (6 wk) after irradiation. CsA treatment inhibits both the positive and negative selection of alpha beta thymocytes in normal young mice as well as in irradiated, T cell-deficient bone marrow-transplanted mice. An increased frequency of "forbidden" V beta 11 T cells is detected in these animals, but it is not clear that these cells are the actual initiators of the inflammatory lesions. In mice of several inbred strains treated by this protocol, striking inflammatory lesions develop in the colon, with less intense, but significant lesions in liver, stomach, and pancreas. Unlike allogeneic graft-vs-host disease, no lesions are found in the small intestine. Examination of these lesions by immunohistochemistry demonstrates that the lesions are composed primarily of T cells and macrophages, with focal aggregates of small B cells present. The same pattern of inflammatory lesions can be adoptively transferred with lymphoid cells from the CsA-treated animals at the peak of lesion development to irradiated syngeneic recipients. The transfer of active lesions is blocked by the co-transfer of normal syngeneic T cells to these recipients. Although similar to the previously described system in rats, these findings emphasize several novel features. In mice, we find an absolute requirement for the elimination of mature T cells from the bone marrow source to develop active inflammatory lesions. The particular tissues affected are also distinctive, especially the unusual feature of severe inflammation in the colon, but no involvement of the small intestine. The mechanism by which the presence of normal T cells suppresses the development of active autoimmunity in this model may have implications for the etiology of localized inflammatory lesions in general.