Specific immunotherapy (SIT) is a mainstay approach in the treatment of allergic diseases. While there are several strong hypotheses that provide an explanation for the success (or lack thereof) of this therapeutic approach, most of these hypotheses are incompletely examined in humans. One of the longstanding observations is that SIT induces enhanced production of specific IgG antibodies but the mechanism by which these antibodies may contribute to the efficacy of SIT is not well understood. This proposal will test th hypothesis that blocking IgG exerts an influence on the human basophil response through cell surface CD32b (FcgRIIb). The limited existing literature testing this hypothesis is contradictory but there is new information that may help to explore this question and account for potential biological variation that may occur in a clinical study of SIT. Preliminary studies in this laboratry demonstrate that the relative proportion of CD32a and CD32b can be altered with cytokine exposure. Existing literature is also ambiguous on the signal transduction mechanisms that may mediate CD32 effects. Therefore, the first aim of this proposal is to expand our knowledge of the regulation of CD32 expression and its signaling mechanisms. This knowledge will be used to further improve on the design and interpretation of a clinical study of SIT that is proposed in thesecond aim of the proposal. The purpose of the clinical study is to provide the patients needed to explore the proposed hypothesis but we will couple the results from the in vitro testing of basophil function to the clinical outcomes of SIT as measured by experimental nasal allergen challenges.
The third aim sets out the in vitro testing that will be done during the clinical trial It will focus on several areas of basophil and CD32 biology; to enumerate the quantity and affinity of blocking IgG isotypes, to anchor the study with a traditional method of measuring blocking antibody effect, to introduce a new method to assess the contribution CD32 to the basophil response, to test the basophil for changes in its phenotype, especially as it relates to components of the CD32 signaling pathways and to enumerate the patients' CD32 genotype since it is now apparent that polymorphisms alter CD32 binding to IgG. It is expected that with this new information in hand, we will be able to demonstrate that CD32 participates in blocking antibody effect or understand why it does not.
Treatment of allergic diseases often includes specific immunotherapy (SIT) but the mechanisms responsible for success using this treatment are not yet well understood. Since there is considerable effort to improve SIT, it would stand to reason that a better understanding of its mechanisms would be helpful. This proposal will examine a longstanding hypothesis of SIT that has yet to studied and validated in humans.
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