The overall aim of this proposal is to characterize and define the mechanism behind the adjuvant activity of Neisserial porins by extending our work regarding the effect of the porins on antigen presenting cells. The Neisserial porins to be used are protein IA (PIA) and protein IB (PIB) from the gonococcus and class 1 or 3 proteins from the meningococcus (C1 and C3 respectively). Neisserial porins have been investigated as adjuvants in vaccines using pneumococcal polysaccharide, Hemophilus polysaccharide (currently in use), malarial peptides, human gangliosides (as anti-melanoma vaccines), etc. as antigens. Understanding the mechanism behind the Neisserial porins immuno-potentiating ability will aid in the more effective use as adjuvants. Neisserial porins can increase the expression of the ligand B7-2 on B lymphocytes, which is an important mediator of T lymphocyte costimulation, and induce B cells to proliferate and to secrete immunoglobulin nonspecifially. To aid in investigating the mechanism of the porins immuno-potentiating ability and to connect the effect of the porins on antigen presenting cells to their adjuvant activity, this proposal with the following aims is submitted.
The first aim will be to bridge the in vitro effect of the porins on B cells, as characterized by increased B7-2 expression, to the porins' adjuvant activity. This will be accomplished by using the porins as adjuvants in immunizations of B7-2 knockout mice, nude mice of CD3 transgenic mice.
The second aim will be to discern if the porins can increase specific in vitro antibody towards bacterial capsular polysaccharides, again bridging the finding that porins can activate B cells to the porins's adjuvant activity. In addition, this aim will define the role of cytokines in the porins' adjuvant ability.
The third aim will be to continue our studies on the ability of porins to stimulate murine B cells and discern if they affect other murine antigen presenting cells (macrophages/monocytes and dendritic cells) in a similar manner.
The final aim will be to investigate whether Neisserial porins have a similar manner.
The final aim will be to investigate whether Neisserial porins have a similar effect on human antigen presenting cells. If these aims are accomplished, the understanding of the Neisserial porins' effects on lymphocytes and antigen presenting cells will be greatly enhanced, and the use of the porins and other microbial substances as adjuvants can be improved.
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