This grant describes studies designed to increase our understand of the elements involved in the pathogenesis of human allergic disease, with a long range goal of improving the therapy of these illnesses. More specifically, we hypothesize that while both IgE containing cells-the basophils 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. The basophil generates and is influenced by a variety of cytokines and our central focus is to understand the regulation of cytokine release as compared to the release of the more acute mediators, histamine and leukotrienes. Basophils release far more IL-4 and IL-13 than lymphocytes. These cytokines play an important role by causing B cells to make IgE and T cells to assume the proinflammatory phenotype (Th2). They also induce the adhesion molecules which lead to the accumulation of eosinophils, basophils and lymphocytes at the site of allergic inflammation. We have demonstrated 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. We believe that these differences will have implications for the therapy of disease. This grant also funds studies which test the relevance of these in vitro studies in in vivo antigen challenge models involving the upper airways and skin. We also propose analysis of the changes induced by two powerful new therapeutic agents. The first involves treatment with humanized anti-IgE which decreases the serum IgE level by more than 99 percent and which reduces the number of IgE receptor molecules on basophil and mast cell surfaces by a like amount. The second involves immunotherapy involving allergen coupled to oligonucleotide sequences derived from bacterial DNA. This modified allergen has the characteristics which have been sought in the field for decades. That is, the allergenicity of the molecules are decreased while their immunogenicity is increased. This has been demonstrated in mice, dogs, primates and to a limited extent, in man.
| 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 |
