Kinetics and cellular origin of cytokines in the central nervous system: Insight into mechanisms of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2(b)) mice is characterized by early (day 12) acute paralysis, followed by a sustained chronic clinical course that gradually stabilizes. Extensive inflammation and demyelination coincide wit h clinical signs of disease. To identify the mechanisms of these processes, individual proinflammatory and anti-inflammatory cytokines and chemokines were studied. Sensitive single-cell assays were utilized to determine the c ellular origin and kinetics of cytokine production in the CNS, Immunization with MOG(35-55) peptide resulted in priming of both Th1 (lymphotoxin, IFN- gamma, and TNF-alpha) and Th2 (IL-4) cells in the spleen. However, only Th1 cells were apparent in the CNS, CD4 T cells that produced IFN-gamma or TNF -alpha were present in the CNS by day 7 after immunization with MOG(35-55), peaked at day 20, and then waned. TNF-alpha was also produced in the CNS b y Mac-1(+) cells. On days 7 and 10 after immunization, the TNF-alpha-produc ing Mac1(+) cells were predominantly microglia, By day 14, a switch occurre d in that the Mac1(+) TNF-alpha-producing cells had the phenotype of infilt rating macrophages, RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 chemokine mRNA were detected in the CNS by day 8 afte r immunization. The early presence of monocyte chemotactic protein 1 (MCP-1 ) in the CNS provides a mechanism for the recruitment of macrophages, These data implicate TNF-alpha production by a continuum of T cells, microglia, and macrophages at various times during the course of disease. The importan ce of Th1 cytokines is highlighted, with little evidence for a role of Th2 cytokines.