Anti-Inflammatory mechanisms of soybean-derived Bowman-Birk protease inhibitor

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DESCRIPTION (provided by applicant): Bowman-Birk Inhibitor (BBI) is an orally active serine protease inhibitor derived from soybeans. BBI concentrate (BBIC) is an extract of soybeans enriched in BBI. In human trials for non-neurological autoimmune disorders, BBIC has been shown to exert potent anti-inflammatory effects without associated toxicity. We have shown that in several rodent models oral BBI/BBIC dramatically reduced autoimmune inflammation of the central nervous system. It is of major significance that after disease onset, when clinical deficits have already developed, administration of BBI rapidly ameliorated clinical signs and prevented disease progression. This feature of BBI therapy is central to its suitability for treating patients who have already shown clinical signs of disease. Even though BBIC has been clinically tested, mechanisms of its anti-inflammatory action are poorly understood in both neurological and non-neurological autoimmune diseases. Here we propose to investigate effects of BBI on immune cells in vivo and in vitro using a mouse model of multiple sclerosis (MS) mediated predominantly by CD4+T cells, and a model of diabetes mediated predominantly by CD8+T cells. In specific aim 1 we will test the hypothesis that increase in IL-10 production is an important mechanism for anti-inflammatory effects of BBI in EAE. This hypothesis is based on our discovery that BBI induces IL-10 production by immune cells in vivo and in vitro. It has been shown that BBI inhibits antigen processing, but its effect on functions of antigen presenting cells is unknown. In aim 2 we will test the hypothesis that BBI suppresses antigen presentation. Thus far, there is no study that addresses direct effects of BBI on T cells. Taking in account the crucial role of T cells in adaptive immunity, in aim 3 we will test the hypothesis that BBI directly suppresses T cells. We expect that these studies will yield in depth insights into mechanistic aspects of anti-inflammatory actions of BBI, and facilitate its use as a supplementary treatment for MS, as well as other inflammatory conditions. Public Health Relevance: Bowman-Birk Inhibitor (BBI) is an orally active protease inhibitor from soybeans. In human trials for autoimmune disorders, BBI has been shown to have anti-inflammatory effects without associated toxicity. Even though BBI has already been clinically tested, mechanisms of its anti-inflammatory action are poorly understood. Here we propose to investigate effects of BBI on immune cells in experimental models of multiple sclerosis and diabetes. In our previous study we discovered that BBI increases production of interleukin 10 (IL-10). IL-10 has well known anti-inflammatory properties, and we will investigate if this molecule plays a role in beneficial effects of BBI. Published data and preliminary studies indicate that BBI has an effect on two crucial types of immune cells; so called antigen presenting cells and T cells. The second portion of this proposal is dedicated to mechanistic studies of effects that BBI has on these cells. We believe that these studies will provide in depth insights into anti-inflammatory actions of BBI, and facilitate its use as a supplementary treatment for inflammatory diseases.