Critical Points of Tumor Necrosis Factor Action in Central Nervous System Autoimmune Inflammation Defined by Gene Targeting

Abstract

Tumor necrosis factor (TNF)–dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (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 initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During 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 indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed 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 occurred in both WT and TNF−/− mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.

Central nervous system gene therapy with interleukin-4 inhibits progression of ongoing relapsing–remitting autoimmune encephalomyelitis in Biozzi AB/H mice

“…26 On the other hand, there are data indicating that activated microglia may limit CNS inflammation by re-stimulating in situ 'anti-inflammatory' Th2 responses. 21 Although we recorded an increased number of CNSinfiltrating T cells in IL-4-treated versus control mice, we can exclude the possibility that the protective effect of IL-4 was due to an increased recruitment of Th2 'protective' T cells since we did not observe changes in mRNA levels of Th1 (ie TNF␣) and Th2 (ie IL-4) cytokines 27 in CNSinfiltrating cells from IL-4-treated versus control mice.…”

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

“…Several previous studies have shown that following immunization with myelin antigens, TNF/p55TNFR signaling functions to accelerate the onset of autoimmune inflammation in the CNS [48][49][50]. Recently, we have obtained additional evidence suggesting an autoimmune and disease suppressive role for TNF in the chronic development of EAE [34].…”

“…In the Tnf -/-group, onset of clinical symptoms is delayed, starting from 16 days post-immunization. Despite the delayed onset, which is typical in the absence of TNF [48], Tnf -/-mice display clinical EAE that progresses into a chronic non-remitting disease (clinical score 2). Interestingly, onset of EAE is fully suppressed in Tnf tm/tm mice, and chronic progression to EAE does not develop (Fig.…”

Augmentation of natural immunity to a pro-inflammatory cytokine (TNF-alpha) by targeted DNA vaccine confers long-lasting resistance to experimental autoimmune encephalomyelitis

“…TNF-␣ is produced by activated T cells (mostly Th1) and macrophages, and its elevated expression at the site of inflammation occurs during the critical phase of disease, 11 at the time when the 'secondary influx' of leukocytes is apparent. 3 Except for a single recent study carried out in genetically modified animals, 36 all investigators agree that TNF-␣ contributes to the pro-inflammatory process in EAE, and probably MS. 25,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] Thus, inhibition of TNF-␣ activity by either neutralizing antibodies or soluble TNF receptor therapy, effectively prevents, or even reverses EAE. 25,42,45,[47][48][49][50][51] Overexpression of TNF-␣ in the CNS aggravated the dis-ease, 46 whereas genetically impaired expression of this gene inhibited the development and progression of disease.…”

“…25,42,45,[47][48][49][50][51] Overexpression of TNF-␣ in the CNS aggravated the dis-ease, 46 whereas genetically impaired expression of this gene inhibited the development and progression of disease. 43 Its pivotal role in T cell-mediated autoimmune diseases makes TNF-␣ a favorable target for clinical trials aiming at inhibiting MS and rheumatoid arthritis (RA). From a clinical perspective, a major disadvantage in treating these chronic diseases with xenogenic neutralizing antibodies, or even chimeric humanized antibodies (reviewed in Ref.…”