Current studies have indicated that antibodies directed against the stalk region of CD23 causeenhancement of IgE synthesis in both the human in vitro and mouse in vivo systems. CD23transgenic mice, which overexpress CD23 on all lymphocytes and follicular dendritic cells, exhibitdrastically reduced IgE production in both helminth and alum/Ag models. The data suggest a modelwhere the role of CD23 is initially to serve as a component of innate immunity to signal for IgE productionby becoming destabilized and cleaved, and later by its overexpression at the cell surface to downmodulateIgE production. This project will investigate the mechanism(s) of these effects.
Aim#1 examines the mouse system where the destabilizing mAb 19G5 gives enhanced IgE synthesis in vivo.Importantly, the metalloprotease, ADAM10, has been identified as the primary CD23 sheddase in mouseand humans. The role of ADAM10 in allergic disease will be modeled by making transgenic mice thatoverexpress ADAM10 or make a dominant negative ADAM10. In addition, we will examine themechanism for the 19G5-dependent enhancement of IgE production by investigating the association ofCD23 with another negative signaling molecule, LAX, which has recently been shown to both modulateCD23 expression and regulate IgE levels.
Aim#2 will investigate the affect of CD23 overexpression andCD23 destabilization on the mouse asthma model with respect to both modulation and exacerbation ofdisease. We will utilize both IgE and the new ADAM10 transgenics to evaluate the mechanism(s) of thesuppression of eosinophilia as well as the capacity of CD23 to modulate the asthma phenotype. Inaddition, Lyn deficient mice will be used to evaluate the capacity of CD23 to modulate the extremeasthma phenotype.
Aim#3 will investigate the human in vitro IgE synthesis models with respect to themechanisms involved in IgE synthesis enhancement, seen with anti-stalk antibodies and synthesissuppression, seen with certain anti-lectin mAbs. The importance of ADAM10 in human CD23 cleavageand IgE production will also be explored as will the involvement of LAX. Finally, we will determine if IgEproduction by B cells obtained from normal and allergic subjects is affected differently by destabilizationor stabilization of CD23. In summary, these studies examine the mechanism of action of a naturalregulator of IgE production, CD23, with the objective of developing protocols to enhance CD23expression and thereby diminish IgE production, and, by analogy, allergic diseases such as asthma inwhich IgE plays a dominant role.
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