CYTOKINE-MEDIATED REGULATION OF CHRONIC INTESTINAL HELMINTH INFECTION

Most inbred strains of mouse infected with the intestinal nematode Tri churis muris are resistant to infection expelling the parasite before adult worms establish. However, a few susceptible strains exist that a re incapable of worm expulsion and harbor chronic infections of mature adult worms. Analyses of in vitro cytokine production by cells from t he draining lymph node (mesenteric lymph node) have indicated that exp ulsion phenotype is tightly correlated with the selective expansion of helper T cells (Th) of the Th1 or Th2 cell subset within the mesenter ic lymph node, resulting in susceptibility and resistance to T. muris, respectively. We have now confirmed and extended our in vitro observa tions in a series of experiments involving the in vivo manipulation of host cytokine levels. Depletion of interferon (IFN)-gamma in normally susceptible mice resulted in expulsion of the parasite, representing the first evidence for a role for IFN-gamma in the establishment of ch ronic helminth infection. Blocking interleukin (IL)-4 function in norm ally resistant animals prevented the generation of a protective immune response allowing adult stages of the parasite to develop. Conversely the administration of IL-4 to a normally susceptible host facilitated expulsion and indeed enabled established adult worms to be expelled w hen administered late in infection. In all cases assessment of a varie ty of in vivo parameters indicative of a Th1- or Th2-type response (pa rasite-specific immunoglobulin (Ig) G2a and the parasite-specific IgG1 , total IgE levels and intestinal mastocytosis, respectively) demonstr ated that the in vivo modulation of a Th1- or Th2-specific cytokine al lowed the reciprocal Th cell subset to expand and become dominant with dramatic consequences for worm expulsion.