The primary long term objective of this project is to determine why schistosome eggs induce predominantly Th2 responses. Parasite eggs form the focus of the granulomatous lesions which represent the major pathological manifestation of infection with Schistosoma mansoni. In mice infected with S. mansoni (a good model of human schistosomiasis), granuloma formation is CD4+ T helper (Th) cell-dependent. Since the principal T cell response occurring at the time of granuloma formation is Th2-like, it is probable that this Th subset is involved in the expression of immunopathology. Additionally, Th2 cells also appear to be responsible for a potentially undesirable downregulation of Th1 function in infected mice. The development of the observed Th2 response is intimately associated with the egg antigen stimulus and does not occur in animals with non-reproductive attenuated or single sex infections. Furthermore, popliteal lymph nodes is normal mice inoculated in the footpads with isolated eggs (""""""""footpad model"""""""") exhibit potent Th2 responsiveness to egg antigens and demonstrate downregulated Th1 effector functions. In light of these points, the specific aims of the project are: to use the footpad model to establish the relative ability of egg versus schistosomula or adult parasite antigens to induce skewed Th responses; use protein purification techniques in combination with the footpad model to identify the major antigens within eggs to which Th cells from mice primed with whole eggs respond; determine whether these antigens can independently induce Th2 responses or whether something additional, such as the egg shell or the presentation of egg antigens as a relatively large antigen """"""""bolus"""""""" or by a particular subpopulation of antigen presenting cells, is crucial in this respect; use specific reagents to establish the stage specificity of egg Th2 antigens; and determine whether or not eggs contain a T cell mitogen by assessing the ability of egg molecules to stimulate Th cells from normal animals. Cytokine assays, immune system cell separations/depletions, flow cytometry, immunochemistry, protein chemistry and mRNA analyses will be used to accomplish these aims.
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