Characterization of human IgA-inducing protein

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Over the last several years there has been a great deal of progress in characterizing the role of dendritic cells (DCs) in the activation and modulation of B cells. DC-secreted chemokines can induce B cell trafficking to the lymph nodes. DC-produced survival factors such as BAFF and APRIL have been shown to be essential for B cell maturation, but have also been implicated in class-switch recombination and B cell lymphoma survival. Recently added to this list of DC-derived factors effecting B cells is IgA-inducing protein (IGIP). Here we characterize production of IGIP by human DCs, and examine its capacity to induce IgA class switching and differentiation of naïve B cells in vitro. Monocyte derived DCs were cultured in vitro with TLR agonists (3,4,5, and 9), other factors including CD40L, GM-CSF, and IL-4, and the neuropeptide vasoactive intestinal peptide (VIP). Under in vitro stimulation with VIP and CD40L, IGIP mRNA expression was up-regulated as much as thirty five-fold above non-stimulated samples within 12-48 hours. Naïve B cells cultured with exogenous rhIGIP produced IgA in significantly greater quantities than non-stimulated controls, and I demonstrated that IGIP stimulation drives the production of µ-α switch circles from IgM+/IgD+ naïve human B cells, indicating its role as an IgA switch factor. Additionally, the capacity of IGIP to elicit a mucosal IgA response was evaluated as part of a vaccine preparation, using a putative HIV-1 vaccine in a SCID-hu mouse model. SCID-hu mice were immunized with a dextran-based HIV-1 vaccine carrying gp120, with or without IGIP, and both serum and mucosal antibody responses were measured. While protection was sporadic, robust antibody responses were detected at both locations.