Cytokine-mediated regulation of chronic intestinal helminth infection.

Abstract

Most inbred strains of mouse infected with the intestinal nematode Trichuris muris are resistant to infection expelling the parasite before adult worms establish. However, a few susceptible strains exist that are incapable of worm expulsion and harbor chronic infections of mature adult worms. Analyses of in vitro cytokine production by cells from the draining lymph node (mesenteric lymph node) have indicated that expulsion phenotype is tightly correlated with the selective expansion of helper T cells (Th) of the Th1 or Th2 cell subset within the mesenteric lymph node, resulting in susceptibility and resistance to T. muris, respectively. We have now confirmed and extended our in vitro observations 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 chronic helminth infection. Blocking interleukin (IL)-4 function in normally 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 when administered late in infection. In all cases assessment of a variety of in vivo parameters indicative of a Th1- or Th2-type response (parasite-specific immunoglobulin (Ig) G2a and the parasite-specific IgG1, total IgE levels and intestinal mastocytosis, respectively) demonstrated that the in vivo modulation of a Th1- or Th2-specific cytokine allowed the reciprocal Th cell subset to expand and become dominant with dramatic consequences for worm expulsion.

Interleukin 1 plays a major role in the development of Th2‐mediated immunity

“…The naturally occurring mouse counterpart Trichuris muris has provided much information on the immunoregulatory mechanisms underlying resistance and susceptibility to this parasite. A number of studies have shown that the ability to develop resistance or chronicity is dependent on Th2 and Th1 cells, respectively [1,2,4,25]. Our data now demonstrate that IL-1 is a crucial component in the Th2 cytokine cascade that leads to protective immunity and resistance.…”

“…Resistance to T. muris, as measured by worm expulsion, is known to be Th2 dependent [1][2][3][4][5][6]. As expected, the WT mice developed resistance to T. muris infection and expelled the majority of worms before day 18 p.i.…”

“…WT mice on a C57BL/6 background are normally resistant to T. muris infection and expel the worms within 18-21 days. The expulsion is accompanied by elevated expression of Th2-type cytokines (IL-4, IL-13 and IL-9) in the MLN [1][2][3][4][5][6]. However, when we infected IL-1a and IL-1b KO mice, on a C57BL/6 background, these mice were unable to expel the worms and developed chronic infections.…”

“…These early events in an immune response direct the development of T helper (Th) cell subsets and subsequently affect the outcome of infection. In many helminth infections, including Trichuris muris, immune-mediated worm expulsion is clearly dependent on a Th2 type of response involving interleukin (IL)-4, IL-9 and IL-13, while susceptibility to chronic infection is mediated by IL-18, IL-12 and IFN-c [1][2][3][4][5][6].…”

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

“…These changes in the environment of the large intestine are driven by the Th2 cytokine IL-13 and to a lesser extent 24]. In contrast, mice that develop a Th1 response remain susceptible and infection proceeds to chronicity [25]. In this context, IL-10-deficient mice infected with T. muris mount a Th1 immune response and develop a severe inflammation of the large intestine, resulting in the death of the mice [26].…”