T-INDEPENDENT IGA INDUCTION AND HIV-1 VACCINATION

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DESCRIPTION: (Adapted from Applicant's Abstract) Antibodies of the IgA isotype are believed to be the major mediator of the B cell derived immunity at mucosal sites. Induction of the antigen-specific IgA in rectal and genital mucosa can be particularly important in protection against sexually transmitted pathogens, such as the human immunodeficiency virus (HIV-1). For years, investigations focused primarily on the T-dependent route of B-cell activation that leads to induction of antigen specific IgA. In contrast, little effort has been performed to explore the T-independent route of IgA induction. It has been known for decades that some thymus-independent antigens can induce IgA responses. Recent establishment of a strain of T-cell deficient mice (C57BL, alpha beta/ gamma delta T-cell receptor knock-out, -/- mice) provided us a simplified model to investigate the T-independent B-cell responses in vivo in the absence of any T cell. When a specific microbial polysaccharide antigen, alpha (1-6) dextran, was injected into these mice, a large number of antigen-specific B cells, predominately of the IgA isotype, were elicited. The number of antigen specific IgA-secreting cells in spleen is about 30 fold higher than those in normal mice or mice injected with a structurally distinct polysaccharide, B1355S. These findings illustrated clearly the presence of a T-independent (TI) route of IgA induction in living animals and identified a polysaccharide antigen, alpha (1-6) dextran, as a potent stimulator of IgA-secreting B cells. In this proposal, we plan to investigate: 1) Can alpha (1-6) dextran serve as a carrier and/or adjuvant to elicit IgA responses to other antigenic determinants? 2) Can alpha (1-6) dextran-containing conjugates facilitate IgA responses to the gp120 glycoprotein of HIV-1? 3) What are the optimal route(s) of administration of these antigens to elicit antigen specific IgA at mucosal sites? With the unique T-independent characteristics, this category of vaccines can be effective not only in normal individuals but also in AIDS patients whose T-cell systems were severely impaired, serving as therapeutic vaccinations against HIV. The principle may also be applied to develop vaccines against opportunistic infections occurring frequently in AIDS patients and in other T-cell deficient syndromes.