TNF-alpha, nitric oxide and IFN-gamma are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii

We previously reported that genetic susceptibility of mice to peroral infec tion with T. gondii is associated with CD4(+) T cell-dependent, interferon (IFN)-gamma-mediated necrosis of their small intestine. We examined the rol e of tumour necrosis factor (TNF)-alpha and nitric oxide (NO), in addition to IFN-gamma. At 7 days after infection, a marked increase in CD4(+) T cell s was observed in lamina propria mononuclear cells (LPC) of the small intes tine as compared with normal mice, and significantly greater amounts of mRN A for IFN-gamma, TNF-alpha, and inducible NO synthase (iNOS) were detected in LPC of the small intestine of infected than uninfected animals. Treatmen t of infected mice with anti-TNF-alpha monoclonal antibody (mAb) or the iNO S inhibitor aminoguanidine, prevented necrosis and prolonged time to death. Infected iNOS-targeted mutant mice did not develop the disease whereas inf ected, control mice did. Treatment with anti-TNF-alpha mAb did not affect t he expression of IFN-gamma in the LPC but inhibited expression of iNOS in t he infected mice, indicating the role of TNF-alpha in the induction of iNOS . These results suggest that NO induced by a combination of IFN-gamma and T NF-alpha through activation of iNOS is a critical mediator of intestinal pa thology and contributes to early mortality in genetically susceptible mice.