An increased incidence of inflammatory and autoimmune diseases in the developed countries is suggested due to good sanitation called the hygiene hypothesis. Recent reports that patients with inflammatory autoimmune diseases rheumatoid arthritis (RA) have decreased fecal levels of certain commensal bacteria such as Prevotella and Bifidobacetrium further support this hypothesis. Thus, it is hypothesized that intestinal microbes with the innate immune system might be a critical epigenetic factor modifying autoimmune diseases such as RA and Multiple Sclerosis (MS). The intestinal microbiota act as the primary agent in the development of the postnatal immune system and expansion of T regulatory cells. In patients with RA and MS, putative Treg cells have been demonstrated in peripheral blood although they are defective functionally. These observations suggest that commensal bacteria can be used as probiotics to treat inflammatory and autoimmune disease. Rheumatoid arthritis and MS are both multifactorial diseases and require interaction between genetic and environmental factors for predisposition. Among genetic factors, association with certain class II molecules is the strongest factor for both diseases. Rheumatoid arthritis is associated with the presence of DR4/DQ8 while MS is associated with HLA-DR2, 3, 4, and DQ6, DQ8. A role of CD4 T cells and B cells has been suggested based on the cytokines and success of the anti-cytokine and anti-B cell therapies in both diseases. Recently, we isolated Prevotella histicola, anaerobic commensal bacteria of the human gut from the bowel of a patient. We propose that P. histicola induced innate/adaptive immune responses in the gut cause induction of anti-inflammatory cytokines/chemokines, Tregs, and subsequent immune tolerance in periphery leading to suppression of collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE). In this proposal we will investigate the ability of P. histicola to modulate immune response and clinical disease in an animal model of arthritis, (collagen-induced arthritis (CIA), and MS (experimental autoimmune encephalomyelitis (EAE). We will use both preventive and therapeutic protocols to define the immunomodulatory effect of the bacteria in these models. Further, we will define the mechanism of action of probiotics-mediated suppression of autoimmunity, especially the role of mucosal immune response and regulatory T cells. We will use our novel humanized HLA class II transgenic mice expressing human HLA-DR3 or DR4 and DQ8 in mice lacking endogenous class II genes as an animal model for MS and RA. Immunization of DR4/DQ8 mice with type II collagen leads to the development of CIA, and immunization of DR3/DQ8 mice with myelin proteolipid protein leads to development of EAE. Both diseases develop organ-specific pathology similar to one observed in their respective human diseases. Our preliminary data using P. histicola in these models has shown that bacterium possesses anti-inflammatory properties and indicates that it can be used as a probiotic for treatment of autoimmune diseases. This is the first reported use of Gram-negative commensal bacteria as probiotics. Treatment of these disorders generally relies on immunosuppressive drugs, which lack specificity of action and can have serious side effects. A novel approach for the treatment of such diseases is to exploit the immunomodulatory function of commensal bacteria, which might be relevant to human inflammatory diseases and may pave the way for a safe and novel therapeutic option. If successful, this therapy can be used to treat not only RA and MS, but other inflammatory and autoimmune diseases, too.
|Effective start/end date||1/1/09 → 8/14/13|
- Congressionally Directed Medical Research Programs: $597,190.00
- U.S. Department of Defense: $597,190.00