This grant describes studies designed to increase our understanding of the elements involved in the pathogenesis of human allergic disease, with the long range goal of improving the therapy of these illnesses. More specifically we hypothesize that, while both IgE-containing cells--the basophil and mast cells--play a role in the allergic diathesis, the basophil plays the more prominent role in the chronic allergic processes which account for most of the morbidity and mortality. We intend to study these disease--asthma, rhinitis, atopic dermatitis--and a model of these diseases, the late phase reaction which occurs after antigen challenge of the skin or the upper and lower airways.
The Specific Aims focus on the observations that basophils generate both acute proinflammatory mediators, such as histamine and LTC4, and mediators which are secreted hours after the acute response, the cytokines. Of those we have focused on interleukin 4, a cytokine which causes B cells to make IgE, T cells to assume the proinflammatory TH2 phenotype and induces the adhesion molecules which lead to the accumulation of eosinophils, basophils and lymphocytes at loci of allergic inflammation. We speculate that the mechanisms involved in the release of these two classes of mediators are quite different, and consequently that the pharmacologic control of their release will be different and finally, that these differences will have implications for the therapy of these diseases. We further postulate that a prominent basophil secretagogue is another cytokine designated as """"""""histamine releasing factor"""""""" (HRF) which we have found to cause release by an IgE-dependent mechanism. HRF has been cloned we plan to develop antibodies against it to probe its importance in several types of allergic disease. This HRF discriminates between two types of IgE, only one of which supports mediator release: We will define the chemical basis of this difference. The bulk of these studies are in vitro and involve basophils but human mast cells will also be subjected to parallel studies insofar as is possible. Finally, we will test the relevance of these in vitro studies in our antigen challenge models and in diseases of the upper and lower airways and in skin. If our hypotheses are correct and the basophils play a central role in chronic allergic disease, then understanding the mechanisms and pharmacologic control of the two types of mediators generated by this cell, as well as the mast cell, should lead to important therapeutic advances.
| Hubbard, W C; Bickel, C; Schleimer, R P (1994) Simultaneous quantitation of endogenous levels of cortisone and cortisol in human nasal and bronchoalveolar lavage fluids and plasma via gas chromatography-negative ion chemical ionization mass spectrometry. Anal Biochem 221:109-17 |
