CHARACTERIZATION OF TUMOR NECROSIS FACTOR-DEFICIENT MICE

Although tumor necrosis factor (TNF) initially came to prominence beca use of its anti-tumor activity, most attention is now focused on its p roinflammatory actions. TNF appears to play a critical role in both ea rly and late events involved in inflammation, from localizing the noxi ous agent and amplifying the cellular and mediator responses at the lo cal site and systemically, to editing (e.g., apoptosis) injured cells or effete immune cells and repairing inflammatory damage. We have gene rated mice deficient in TNF (TNF-/- mice) and have begun to examine th e multiple functions attributed to TNF, TNF-/- mice develop normally a nd have no gross structural or morphological abnormalities, As predict ed, they are highly susceptible to challenge with an infectious agent (Candida albicans), are resistant to the lethality of minute doses of lipopolysaccharide (LPS) following D-galactosamine treatment, have a d eficiency in granuloma development, and do not form germinal centers a fter immunization, Phagocytic activity of macrophages appears relative ly normal, as do T cell functions, as measured by proliferation, cytok ine release, and cytotoxicity, B cell response to thymus-independent a ntigens is normal, but the Ig response to thymus-dependent antigen is reduced. Surprisingly, cytokine production induced by LPS appears esse ntially intact, with the exception of reduced colony-stimulating facto r activity. Other unexpected findings coming from our initial analysis are as follows. (i) TNF has low toxicity in TNF-/- mice. (ii) TNF-/- mice show an anomalous late response to heat-killed Corynebacterium pa rvum. In contrast to the prompt response (granuloma formation, hepatos plenomegaly) and subsequent resolution phase in C. parvum-injected TNF +/+ mice, similarly treated TNF-/- mice show little or no initial resp onse, but then develop a vigorous, disorganized inflammatory response leading to death, These results suggest that TNF has an essential home ostatic role in limiting the extent and duration of an inflammatory pr ocess-i.e., an anti-inflammatory function, (iii) In contrast to the ex pectation that TNF+/+ mice and TNF+/- mice would have identical phenot ypes, TNF+/- mice showed increased susceptibility to high-dose LPS let hality, increased susceptibility to Candida challenge, and delayed res olution of the C. parvum-induced inflammatory process, indicating a st rong gene dose requirement for different actions of TNF.