INTERLEUKIN-12 PROMOTES A CHRONIC INTESTINAL NEMATODE INFECTION

Resistance and susceptibility to the intestinal parasite Trichuris mur is has been shown to be due to a dominant T helper 2 (Th2) and a domin ant Th1 response, respectively. The factors determining the initial po larization of the immune response remain largely unresolved, although the cytokine environment at the time of antigen presentation clearly p lays an essential role. Interleukin (IL)-12, a cytokine produced mainl y by macrophages, dendritic cells, and other monocytes has been shown to be important in driving a strong Th1 response by stimulating the pr oduction of interferon (IFN)-gamma from natural killer and Th0 cells a nd therefore forms a link between the innate and adaptive immune syste m. IL-12 has been shown to play an important role in resistance to a n umber of intracellular pathogens, including Listeria and Leishmania. I t has also been proposed as an anti-tumor agent and for use in the tre atment of HIV. Conversely, IL-12 has been shown to prolong the surviva l of Nippostrongylus brasiliensis and to accelerate autoimmunity. Our studies demonstrate that by driving a strong Th1 response, IL-12 promo tes chronic T. muris infection when given to normally resistant BALB/K mice. Parasite-specific IgG2a, a Th1 parameter of infection, was grea tly up-regulated, whereas some Th2 parameters of infection were down-r egulated. IL-12 treatment could be delayed until 1 week after infectio n had started and still promote a strong Th1 response. The actions of IL-12 in promoting a chronic infection were IFN-gamma dependent as an anti-IFN-gamma mAb abrogated the effects of IL-12.