DIFFERENTIAL EXPRESSION OF INFLAMMATORY CYTOKINES PARALLELS PROGRESSION OF CENTRAL-NERVOUS-SYSTEM PATHOLOGY IN 2 CLINICALLY DISTINCT MODELSOF MULTIPLE-SCLEROSIS

Multiple sclerosis is an immune-mediated demyelinating disease of unkn own etiology that presents with either a chronic-progressive or relaps ing-remitting clinical course. Theiler's murine encephalomyelitis viru s-induced demyelinating disease (TMEV-IDD) and relapsing-remitting exp erimental autoimmune encephalomyelitis (R-EAE) in the SJL/J mouse are both relevant murine CD4(+) T cell-mediated demyelinating models that recapitulate the multiple sclerosis disease phenotypes, To determine t he cellular and molecular basis for these observed differences in clin ical course, we quantitatively analyzed the temporal expression of pro - and antiinflammatory cytokine mRNA expression in the central nervous system (CNS) and the phenotype of the inflammatory mononuclear infilt rates, TMEV-infected SJL/J mice expressed IFN-gamma, TNF-alpha, IL-10, and IL-4 mRNA during the preclinical phase, and their levels continue d to increase throughout the duration of the chronic-progressive disea se course. These data correlated with the continued presence of both C D4+ T cells and F4/80(+) macrophages within the CNS infiltrates. In co ntrast, SJL/J mice with PLP139-151-induced R-EAE displayed a biphasic pattern of CNS expression for the proinflammatory cytokines, IFN-gamma and TNF-alpha, with expression peaking at the height of the acute pha se and relapse(s), This pattern correlated with dynamic changes in the CD4(+) T cell and F4/80(+) macrophage populations during relapsing-re mitting disease progression. Interestingly, IL-4 message was undetecta ble until disease remission(s), demonstrating its potential role in th e intrinsic regulation of ongoing disease, whereas IL-10 was continuou sly expressed, arguing against a regulatory role in either disease. Th ese data suggest that the kinetics of cytokine expression together wit h the nature of the persistent inflammatory infiltrates are major cont ributors to the differences in clinical course between TMEV-IDD and R- EAE.