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Role of the Costimulatory Molecule CD28 in the Development of Lupus in MRL/lpr Mice¹

Yoshifumi Tada^*, Kohei Nagasawa^*, Alexandra Ho, Fumitaka Morito^*, Syuichi Koarada^*, Osamu Ushiyama^*, Noriaki Suzuki^*, Akihide Ohta^* and Tak W. Mak^2,

^* Department of Internal Medicine, Saga Medical School, Saga, Japan; and Amgen Institute, Ontario Cancer Institute, and Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

MRL/Mpj-lpr/lpr (MRL/lpr) mice develop autoimmune disorders, including lymphoproliferation, glomerulonephritis, autoantibody production, and hypergammaglobulinemia. To investigate the role of the costimulatory molecule CD28 in the development of these disorders, MRL/lpr mice lacking CD28 were generated by gene targeting. Compared with CD28^+/+ MRL/lpr mice, CD28^-/- MRL/lpr mice showed decreased lymphadenopathy but increased splenomegaly associated with the expansion of abnormal B220⁺ TCRß⁺ T cells. Although levels of IgM Abs were unchanged in CD28^-/- MRL/lpr mice, the production of anti-DNA IgG Abs and IgG rheumatoid factors were suppressed. IgG deposition in the glomeruli was markedly decreased, and the development of glomerulonephritis was significantly retarded. Furthermore, renal vasculitis and arthritis were absent in CD28^-/- MRL/lpr mice. These results indicate that, although CD28 is not required for the generation of the abnormal T cell population in MRL/lpr mice, it does play an important role in the development of autoimmune disease in these animals.

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