LOCAL TH1 AND TH2 RESPONSES TO PARASITIC INFECTION IN THE INTESTINE REGULATION BY IFN-GAMMA AND IL-4

Control of parasitic infections is dependent on the production of cyto kines that activate mechanisms which limit invasion, reproduction or s urvival of the parasite, In contrast, conditions that induce inappropr iate cytokine responses facilitate the spread of infection and ultimat ely exacerbate the level of disease, Measurement of local cytokine res ponses to different gastrointestinal parasites, such as the intracellu lar protozoan, Cryptosporidium parvum, and luminal dwelling nematodes like Nippostrongylus brasiliensis and Heligmosomoides polygyrus, revea l stereotype response patterns. In general, intracellular parasites st imulate type I responses where IFN-gamma is the predominant immune act ivator, while extracellular parasites stimulate type 2 responses where IL-4 plays a prominent role in elevating humoral immune mechanisms, C ytokines alter cellular function and the milieu of the intestinal lume n to affect the outcome of an infection, The importance of a particula r response during the course of an infection can be studied by selecti ve enhancement with an excess of exogenous recombinant cytokine or cyt okine antagonists, For example, exogenous IL-12 enhances resistance to C. parvum, but suppresses the normally rapid cure of an infection wit h N. brasiliensis. Both mechanisms are dependent on expression of IFN- gamma. At the molecular level, exogenous IL-12 stimulates IFN-gamma pr oduction which elevates a protective type 1 response to C. parvum but converts the normally anti-worm type 2 response to a type 1 response t hat inappropriately regulates the infection. Alternatively, excess IL- 4 plays a prominent role in modulating effector elements that change i ntestinal physiology to create a hostile environment for worm parasite s. Exogenous IL-4 can cure chronic worm infection, while IL-4 antagoni sts interfere with protective responses to infection. These observatio ns provide a paradigm for analysis of stereotype responses to differen t gastrointestinal parasites, and demonstrate how cytokine-induced imm une system-dependent and independent effector mechanisms can limit par asitic infection, while inappropriate cytokine responses can exacerbat e the state of disease.