Asthma and allergic diseases are important health concerns, and mast cells and possibly basophils are themajor effector cells of IgE-mediated immediate hypersensitivy in humans. Previous work by the investigatorsinvolved in Project 1 includes developing tryptase as a clinical marker for mast cell activation; findingactivation of mast cells in the asthmatic airway and during systemic anaphylaxis; identifying two types ofhuman mast cells (MCT and MCTc) based on the protease content of their secretory granules and the surfaceexpression of CD88; discovering the activating form of FcyRII, CD32a, constitutively expressed on thesurface of skin MCTC cells; and finding Syk-deficiency in basophils with the non-releaser phenotype and inmast cells after antigen desensitization in vitro. The three specific aims of the current project are to:1. Test the hypothesis that human mast cells and basophils in vitro undergo cross-desensitization todifferent antigens and heterologous desensitization through FcsRI and FcvRlla. Indeed, preliminarydata suggest that when mast cells of the MCTc type are IgE anti-DNP-sensitized and then desensitizedwith low doses of DNP-BSA, both cross-desensitization and heterologous desensitization occurs.2. Explore in vitro the mechanism(s) for desensitization of human mast cells involving Src and/or Syktyrosine kinases. Although Syk depletion seems likely, the involvement of Lyn and/or Fyn is uncertain.Further, the possibility that subcellular compartmentalization of signaling differs for desensitization andactivation will be examined. Collaborations with Project 3 on studies of Lyn kinase involvement indesensitization, and with Project 4 on the involvement of sphingosine kinase-1 in desensitization ofhuman mast cells and basophils facilitate these mechanistic studies.3. Determine whether penicillin desensitization of human subjects in vivo produces antigen crossdesensitizationof mast cells and basophils and depletes Syk from peripheral blood basophils. Thisclinical study will begin to translate our in vitro findings to the in vivo situation.Clinical tolerance due to desensitization can be distinguished from that due to immunotherapy by its rapidinduction (hours) and short persistence (days) once allergen administration ceases. We hypothesize thatdesensitization targets primarily mast cells and basophils. Understanding more precisely the characteristicsof and the mechanism(s) behind desensitization will enable physicians to better utilize this approach toreduce mast cell/basophil-mediated contributions to asthma and allergic diseases.
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