DIFFERENT IMBALANCES OF CYTOKINES IN NEMATODE INFECTIONS

该项目的长期目标是通过

The long-term objective of this project is to determine the mechanisms by which different nematodes cause opposite effects on the production of mast cells. Nippostrongylus brasiliensis (Nb) and Trichinella spiralis (Ts) cause striking intestinal mastocytosis; by contrast, Nematospiroides dubius (Nd) not only fails to cause mastocytosis but also inhibits the development of mastocytosis following appropriate stimuli. In cultures of normal bone marrow, medium conditioned (CM) by spleen cells of normal mice (Nor-CM) or Ts-or Nb-infected mice (Ts-CM or Nb-CM) supports the development of mast cells from progenitors in bone marrow; medium conditioned by spleen cells of Nd-infected mice fails to support mast cell development in bone marrow cultures and inhibits the activity of active CM. The overall hypothesis for this proposal is that Ts and Nb cause an imbalance of L3T4+ T cells favoring the Th2 subset whereas Nd infection favors the Th1 subset. The effect of such imbalance of T cell subsets is likely to be imbalanced cytokine production leading to stimulation of mast cell and IgE production in Ts- and Nb-infected mice and inhibition of these events in Nd-infected mice. It is proposed that levels of IL-4, a Th2 cell product which stimulates mast cell development and IgE synthesis, will be increased by Ts and Nb but decreased by Nb infection. This hypothesis will be tested by determining the lymphokine profile (IL-2, IFN-gamma, IL-4, IL-5) of Nor-CM, Ts-CM, Nb-CM, and Nd-CM, by assaying for mRNA of these lymphokines in cells of infected animals, by using flow cytometry to identify subsets of L3T4+ cells, and by evaluating the effect of purified or recombinant cytokines and homologous antibodies on mast cell development in culture. Results obtained should be useful in developing strategies for control of mast cell and IgE production in allergic and other disease states.