IMMUNIZATION WITH ANTIGENIZED VECTORS

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DESCRIPTION: (Adapted from the Investigator's abstract): Regulation of IgE production by B cells is orchestrated by Th2 cytokine IL-4, and cognate interaction of B cells and Th2 via CD4O and CD4OL. IL-4 and CD40L mediate IgE gene rearrangement, and activation of IgE-committed B cells. IL-4 in turn sustains IgE production by skewing Th2 development. This paradigm dictates a treatment modality based on measures to diminish endogenous levels of IL-4 and thereby IgE production by IgE-committed B cells. Alternatively, anti-IgE is employed to inhibit IgE production by IgE-committed B cells. Studies from our laboratoryand that of Nisonoff established an animal model of pan-IgE deficiency in mice perinatally immunized with IgE, prior to the onset of self-tolerance to IgE molecules. Anti-IgE was implicated to play an important role in inhibiting IgE production of IgE committed B cells. This applicationwill determine whether therapeutically useful anti-IgE can be elicited in adult mice immunized with IgE B and T cell epitopes in the presence of strong costimulation. Recently, exciting progress has been made in engineering antigenized immunoglobulin vectors that incorporate oligonucleotides corresponding to both B and T cell epitopes, and GM-CSF as costimulator. Importantly, cloned and expressed B cell epitopes exhibit native conformation of the protein antigens, while T cell epitopes can be processed and presented by GM-CSF activated APC. IgE vaccines prepared in the antigenized vector, pCDR3 will be employed in the proposed studies. Our short-term goal is to achieve the following three Aims: Aim I. To Determine Native Conformation IgE B Cell Epitopes, and Induce Pan-IgE Deficiency by Breaking Self Tolerance to IgE B Cell Epitopes in Adult Mice Immunized with IgE Vaccines. Aim II. To Determine Immunodominant, Physiological IgE helper T Cell Epitopes, and Induce PersistentPan-IgE Deficiency by Breaking Self Tolerance to IgE T and B Cell Epitopes in Concert in Adult Mice Immunized with IgE Vaccines. Aim III. To Determine Mechanisms of Anti-IgE-Mediated Inhibition of IgE Production by IgE-CommittedB Cells in vitro.