Characterization of human IgA-inducing protein

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.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Grantor

The University of Texas Medical Branch

Year dc:date.issued

2009

Author dc:creator

• Mark Allen Endsley

Advisor dc:contributor.advisor

• D. Mark Estes, Ph.D.

Committee members dc:contributor.committeemember

• Victor E. Reyes, Ph.D.
• Randall M. Goldblum, M.D.
• Marcus Kehrli, D.V.M., Ph.D.
• Alfredo G. Torres, Ph.D.

• mucosa

Statement dc:rights

• Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.

Language dc:language.iso

eng

Dc Identifier Other

etd-03302009-092938

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/78