1. Physiology & role of innate T cell & B cell subsets in health & diseases including IBD
2. Role of gut microbiota in IBD & colon cancer
3. Rebalancing intestinal pathogenic inflammatory microbial gene products
A diverse community comprising trillions of different microorganisms resides symbiotically within the human gut. These microbes, mostly bacteria, are referred to as “the commensal microbiota”, and are central to the proper metabolism and intestinal immune processes of the host. It is now well appreciated that these intestinal microbes are required for a balanced immune response and that there composition as a group determines the outcome of health versus local and systemic disease. The focus of our laboratory is to identify bacterial gene product(s) that induce either immune regulation or immune stimulation, as well as to study the molecular mechanisms underlying the interactions between bacteria and the host cells of the gastrointestinal tract. With this as our goal, we our currently studying the effects of different members of “the microbiota”, in particular, different strains of lactobacilli and their gene products, on immune homeostasis and its dysfunction that results in autoinflammatory diseases such as inflammatory bowel disease (IBD) and colon cancer. Specifically, we are employing various cellular and molecular techniques to study the bacterial surface layer proteins of the beneficial bacterium, Lactobacillus acidophilus, that interact with various intestinal cell types, including epithelial cells, dendritic cells, and macrophages. We have clearly shown that while the surface molecule, lipoteichoic acid (LTA), of L. acidophilus is strongly involved in pro-inflammatory immune responses, the bacterial surface layer protein A (SlpA) of the same bacterium is anti-inflammatory and induces immune regulation. We have strong data demonstrating the anti-inflammatory functions of Slp A in several experimental models of induced colitis and colon cancer, whereupon both of these disease processes were significantly mitigated with its oral administration. Currently, we are in the process of establishing an immunotherapeutic platform to evaluate the effects of SlpA on existing patient cohorts suffering from IBD or colon cancer.
Various vaccine platforms have been designed and tested for their efficacy against microbial or tumor challenge; however, many of these strategies still need to be refined. The major drawbacks of most available vaccines are limited protection and the requirement for frequent inoculations to confer protective immunity. These limitations have stimulated the development of improved vaccine platforms against important pathogens, including anthrax. An efficacious, safe, and cost-effective oral vaccine should ideally be given in one or more doses to elicit protection. Data show that such a vaccine strategy can be achieved if it is targeted and directed to mucosal dendritic cells, resulting in enhanced immune responses against microbial challenge. To establish an oral vaccine that mobilizes protective humoral and cell-mediated immunity against infection, my laboratory developed a small peptide that binds specifically to dendritic cells, which direct the other cellular components of the immune system, and hence, the resulting immune response. To establish a multivalent vaccine against tumors and/or infectious agents, this small peptide was used to target vaccine subunits to dendritic cells, and can be orally delivered by beneficial gut bacteria, including L. gasseri. Our data demonstrate that this type of needleless oral vaccine elicits not only a robust mucosal response, but also systemic immunity against pathogen and tumor challenge. We are currently further defining this vaccine strategy for Phase 1 clinical trials.