Reversal of Spontaneous Progressive Autoimmune Encephalomyelitis by Myelin Basic Protein-Induced Clonal Deletion

Abstract

Autoimmune encephalomyelitis can be initiated spontaneously and developed progressively in TCR transgenic mice specific for myelin basic protein when exposed to non-sterile environment, thus more closely mimicking human multiple sclerosis. By intravenous administration of myelin basic protein, we succeeded in reversing the clinical and pathological signs of progressive spontaneous disease in these mice. Flow cytometry showed that the majority of transgenic T cells in lymph nodes and spleen as well as spinal cords of treated mice were deleted. Dramatically increased numbers of apoptotic cells were found in peripheral immune organs of treated animals. Proliferative responses of single transgenic T cell to autoantigen were significantly decreased in treated mice, indicating that the remaining T cells were anergic. Moreover, production of both Th1 and Th2 cytokines was suppressed. This study is the first demonstration of reversal of progressive, spontaneous autoimmune disease of the central nervous system, and provides direct evidence that apoptosis-induced clonal deletion, along with anergy of remaining cells, but not Th2 switch, play a major part in the reversal of this disease by intravenous administration of autoantigen.