Tumor necrosis factor alpha is a critical component of interleukin 13-mediated protective T helper cell type 2 responses during helminth infection

In vivo manipulation of cytokine and/or cytokine receptor expression has pr eviously shown that resistance to infection with the caecum-dwelling helmin th Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susce ptibility is associated with a T helper cell type 1 (Th1) cytokine response . Using gene-targeted mice deficient in tumor necrosis factor (TNF) recepto r signaling and anti-TNF-alpha monoclonal antibody treatment, we have exten ded these studies to reveal a critical role for TNF-alpha in regulation of Th2 cytokine-mediated host protection. In vivo blockade of TNF-alpha in nor mally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the d uration of treatment. IL-13-mediated worm expulsion in IL-4 knockout (KO) m ice was also shown to be TNF-alpha dependent, and could be enhanced by admi nistration of recombinant TNF-alpha. Furthermore, TNF receptor KO mice fail ed to expel T. muris, producing high levels of parasite-specific immunoglob ulin G2a and the generation of a predominantly Th1 response, suggesting tha t the absence of TNF function from the onset of infection dramatically alte rs the phenotype of the response. These results provide the first demonstra tion of the role of TNF-alpha in regulating Th2 cytokine-mediated responses at mucosal sites, and have implications for the design of rational therapi es against helminth infection and allergy.