CS-A therapy in MRL-lpr/lpr mice: amelioration of immunopathology despite autoantibody production.
MRL-lpr/lpr mice spontaneously develop massive T cell lymphadenopathy, autoantibodies, and immune-mediated pathology. These mice are thought to be models of various human autoimmune diseases, including systemic lupus, Sjogren's syndrome, and rheumatoid arthritis. We have used cyclosporin A (CS-A) treatment as a tool by which the mechanisms of immune-mediated pathology might be dissected. CS-A was used because of its known preferential inhibition of T cell function and the marked expansion in MRL-lpr/lpr mice of an unusual L3T4-, Lyt-2-, 6B2+ T cell population. CS-A prevented lymphadenopathy and expansion of L3T4-, Lyt-2-, 6B2+ T cells in the peripheral lymph nodes, and also in the thymus. The increased expression of the c-myb and T cell receptor beta-chain genes associated with these unusual cells was also corrected. The finding of increased numbers of L3T4-, Lyt-2-, 6B2+ thymocytes in untreated mice suggests abnormal intrathymic differentiation in lpr/lpr mice, a defect that was corrected by CS-A. Treated mice had a marked decrease in arthritis and glomerulonephritis and significantly prolonged survival. These beneficial effects of CS-A occurred despite a lack of reduction in antibodies reactive with DNA, circulating immune complexes, rheumatoid factor titers, or immunoglobulin concentrations. These results demonstrate that the B cell hyperactivity of MRL-lpr/lpr mice can proceed without the T cell proliferative disease.
D000818:Animals; D000917:Antibody Formation; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D003524:Cyclosporins / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D007674:Kidney Diseases / Q000188:drug therapy; D008198:Lymph Nodes / Q000473:pathology; D008206:Lymphatic Diseases / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013154:Spleen / Q000473:pathology; D013585:Synovitis / Q000188:drug therapy; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000473:pathology
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D003524:Cyclosporins; D011518:Proto-Oncogene Proteins