CRITICAL-POINTS OF TUMOR-NECROSIS-FACTOR ACTION IN CENTRAL-NERVOUS-SYSTEM AUTOIMMUNE INFLAMMATION DEFINED BY GENE TARGETING

Tumor necrosis factor (TNF)-dependent sites of action in the generatio n of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/G mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalo myelitis (EAE) induced by the 35-55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiatio n of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. Durin g this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF-/- mice. However, in the TNF-/- mice, immunohistological analysis of CNS tissue indicate d that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including pa ralysis and widespread CNS perivascular inflammation, eventually devel oped without TNF. TNF-/- and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF-/- mice was only 60% of the course in control mice. Primary demyelination occu rred in both WT and TNF-/- mice, although it was of variable magnitude . These results are consistent with the TNF dependence of processes co ntrolling initial leukocyte movement within the CNS. Nevertheless, pot ent alternative mechanisms exist to mediate all other phases of EAE.