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Department of Epidemiology and Public Health and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
Experimental autoimmune encephalomyelitis induced by myelin
oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2b) mice
is characterized by early (day 12) acute paralysis, followed by a
sustained chronic clinical course that gradually stabilizes. Extensive
inflammation and demyelination coincide with 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
cellular origin and kinetics of cytokine production in the CNS.
Immunization with MOG35–55 peptide resulted in priming of
both Th1 (lymphotoxin, IFN-
, and TNF-
) and Th2 (IL-4) cells in
the spleen. However, only Th1 cells were apparent in the CNS. CD4 T
cells that produced IFN- or TNF- were present in the CNS by day 7
after immunization with MOG35–55, peaked at day 20, and
then waned. TNF- was also produced in the CNS by Mac-1+
cells. On days 7 and 10 after immunization, the TNF--producing
Mac1+ cells were predominantly microglia. By day 14, a
switch occurred in that the Mac1+ TNF--producing cells
had the phenotype of infiltrating macrophages. RANTES, IFN-inducible
protein 10 (IP-10), and monocyte chemotactic protein 1 chemokine mRNA
were detected in the CNS by day 8 after 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- production by a continuum of T cells, microglia, and
macrophages at various times during the course of disease. The
importance of Th1 cytokines is highlighted, with little evidence for a
role of Th2 cytokines.
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