Modulation of Autoimmunity by Linomide treatment or interference with costimulation
Abstract: Linomide is a potent immunomodulator that has been shown to inhibit autoimmunity in several animal models of autoimmune disease. We have approached the cellular and molecular mechanism of Linomide by investigating its effect on thymocyte development and its capacity to modulate the expression of activation markers on antigen presenting cells (APCs). We found that Linomide treatment of mice resulted in a dramatic decrease in thymic cell number with the most profound effect on immature CD4+CD8+ thymocytes. Mature thymocytes were more resistant to Linomide, and exhibited an enhanced proliferation ex vivo after in vivo Linomide treatment. We also found that Linomide treatment resulted in an enhanced surface expression of several activation markers on APCs. The capacity of different Linomide analogues to upregulate MHC class II on the surface of macrophages correlates with the ability to inhibit experimental autoimmune encephalomyelitis, indicating that the effect of Linomide on APCs may be involved in the inhibition of autoimmunity. To evaluate the effect of enhanced APC activity in another model system, we treated mice induced to develop arthritis with an agonistic anti-CD40 monoclonal antibody (mAb). In contrast to the effect of Linomide treatment, anti-CD40 treatment resulted in an aggravated disease development, elevated serum titres of anti-collagen antibody and increased antigen-specific ex vivo IFN-gamma production. To further dissect the role of costimulatory molecules in the development of collagen-induced arthritis (CIA), we treated mice with anti-CD28, anti-CD80+CD86 (anti-B7) or anti-CD152 mAbs. Anti-B7, and to some extent also anti-CD28, inhibited CIA development and resulted in an increased ex vivo IFN-gamma production, whereas anti-CD152 treatment had no effect. Furthermore, anti-B7 inhibited CIA in IFN-gamma-deficient mice as well, indicating that the enhanced production of IFN-gamma observed after anti-B7 treatment of wild type mice, is not responsible for the protective effect of anti-B7. In conclusion, the results described in this thesis support modulation of APCs as an approach for the development of new treatments in the field of autoimmune diseases.
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