The application is a revised competitive renewal application of a grant in its 11th year which has focused on the study of immune dysregulation in multiple sclerosis (MS). Over the past ten years, the investigator has studied T-cell mechanisms in MS using functional and phenotypic analysis of T-cells, T-cell cloning and immune function related to treatment of the disease. In future years, Dr. Weiner wishes to study abnormal IL-12 and IFN-g regulation in MS. MS is postulated to be a TH1 type cell mediated autoimmune disease: IFN-g induces MS relapses and IFN-g is in the inflammatory lesions in the nervous system. Nonetheless, the regulation of IFN-g production in MS and its relationship to the clinical course are not defined. The investigator has found that anti-CD3 induced IFN-g is increased in MS and is not regulated by IL-10. In the revised application, new observations are reported linking IL-12 to increased IFN-g secretion in MS and an in vitro system has been developed which will allow the investigation of mechanisms associated with increased IL-12/IFN-g in MS. Furthermore, an initial link between response to therapy and decreased IFN-g production has been found, and a defect in IL-10 regulation of IFN-g production has been identified.
The aims of the revised application will address the following questions: 1) what is the cell type that produces IFN-g? 2) what is the cell type that produces IL-12? 3) what are the ligand receptor interactions required for IL-12/IFN-g production? 4) what is the mechanism of defective regulation of IL-12/IFN-g secretion by IL-10? 5) what is the linkage of raised anti-CD3 induced IL-12/IFN-g to cytokine profiles of antigen specific cells? 6) is there a genetic linkage of increased anti-CD3 induced IL-12/IFN-g in first degree relatives? 7) is there any link between these findings and disease type and stage in patients followed serially and in response to therapy?
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