| Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2b) mice is characterized by early acute paralysis, followed by a partial, but not complete recovery from the clinical signs of disease. Extensive inflammation and demyelination coincide with the peak of clinical disease, but inflammation in the CNS recedes late in disease. We investigated mechanisms for both the emergence and resolution of inflammation in the CNS, concentrating on the role of antigen presenting cells (macrophages and microglia) in the target organ. These cells, along with T cells, produced high levels of TNF-α in the CNS at distinct times in disease. Microglia, probably activated by T cells, produced TNF-α early in disease, and subsequently TNF-α producing macrophages invaded the CNS. At the peak of disease, macrophages and microglia presented exogenous and endogenous CNS antigens to T cell lines and CNS T cells, resulting in IFN-γ production. After mice had partially recovered from clinical signs of disease, there was a reduction in antigen presenting capability that correlated with decreased MHC-II and B7-1 expression. Interestingly, although CNS APC induced T cell cytokine production, they did not induce proliferation of either T cell lines or CNS T cells. This was due to their production (mainly by macrophages) of nitric oxide (NO). T cell proliferation was restored in the presence of an NO inhibitor, or using CNS APC obtained from iNOS−/− mice. Thus CNS APC, though essential for the initiation of disease, also play a downregulatory role. The mechanisms by which CNS APC limit the expansion of autoreactive T cells in the target organ include their production of NO and their decreased antigen presenting capability late in disease. Other factors studied here that appear to be involved in the resolution of inflammation include ICOS, the receptor for the costimulatory molecule B7H, and the production of Th2 cytokines such as EL-10 and IL-13. These factors may act to downregulate APC function in the CNS. The studies presented in this thesis highlight the central role of antigen presenting cells in controlling the inflammatory process in CNS during EAE. |
