On the role of cytokines and route of antigen delivery on the modulation of experimental autoimmune encephalomyelitis
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Experimental autoimmune encephalomyelitis (EAE) is a mouse model of the human autoimmune disease multiple sclerosis and is caused by myelin-reactive T lymphocytes that recognize antigens embedded within the myelin sheath in the central nervous system. Herein, we describe two aspects of immune modulation that can be utilized to suppress self-reactive T cell activity and reverse the disease. Oral tolerance to protein antigens is a well-established phenomenon that has received recent attention for its potential to induce non-reactivity to self-antigens. We have previously shown that intra-peritoneal injection of myelin oligodendrocyte glycoprotein (MOG) in the context of an immunoglobulin chimera (Ig-MOG) is effective for modulation of myelin-reactive T cells and reversal of EAE. In this study, we sought to determine whether Ig-MOG could reverse EAE when administered as an orally fed regimen. The results show that oral Ig-MOG is able to suppress both MOG peptide and CNS homogenate induced EAE, and does so by down-regulating both Th1 and Th17 responses. The therapeutic effects of Ig-MOG were found to be mediated by antigen presenting cells of the lamina propria, which acquired Ig-MOG induced tolerogenic function that was dependent on antigen-driven T cell contact. This tolerogenic function was mostly mediated by the up-regulation of the suppressive molecule PD-L1, and inhibition of PD-L1 abrogated the ability of oral Ig- MOG to induce tolerance. In sum, this study provides a novel oral treatment regimen for EAE that offers insight for improved treatments for human multiple sclerosis. It has long been known that Th2 cytokines, such as IL-4 and IL-13, can suppress inflammation and modulate EAE. However, the mechanisms by which these cytokines exert their suppressive functions are poorly understood. To better elucidate how Th2 cytokines regulate CNS inflammation, we generated IL-13R1-/- mice and induced EAE. Intriguingly, IL-13R1-/- mice developed early onset and more severe EAE compared to their WT counterparts. The exacerbated disease was characterized by enhanced Th17 and Th1 responses in the lymph nodes and CNS, respectively. The enhanced T cell activity was mediated by IL-13R1-deficient APCs that secreted greater amounts of the pro-inflammatory cytokine IL-6 and induced enhanced T cell proliferation. Bone marrow chimera experiments revealed that the sole APCs responsible for disease exacerbation were the CNS-resident microglia, which displayed enhanced MHC II and CD86 expression upon EAE induction. In sum, this study reveals a novel mechanism for the control of CNS inflammation, in which microglia utilize IL-13R1 to modulate inflammation and control EAE.
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