SUMMARY The human gut is colonized by a large number of microorganisms (~1013 bacteria) that support various physiologic functions. A perturbation in healthy gut microbiome might leads to the development of inflammatory diseases including multiple sclerosis (MS). Therefore, gut commensals can provide promising therapeutic options for treating autoimmune diseases such as MS. We report identification of human gut–derived commensal bacteria, Prevotella histicola, which can suppress an autoimmune disease in HLA class-II transgenic model of experimental autoimmune encephalomyelitis (EAE); an animal model of MS. P. histicola suppresses disease through modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells, and increase in the frequencies of CD4+FoxP3+ regulatory T cells, tolerogenic dendritic cells, and suppressive macrophage. Our study provides evidence that administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in the treatment strategies for MS.

Celiac disease (CD) is a common chronic immune disease triggered by gluten. Gliadin peptides pass through the epithelial layers, either paracellularly or transcellularly, to launch a potent adaptive immune response in the lamina propria. This aberrant immune response leads to diverse gastrointestinal and extra-gastrointestinal symptoms. Currently, the only treatment for CD is a strict lifelong adherence to a gluten-free diet (GFD), which can be challenging. An early effect of gluten in CD is an increase in gut permeability. Larazotide acetate, also known as AT-1001, is a synthetic peptide developed as a permeability regulator primarily targeting CD. In vitro studies indicate that larazotide acetate is capable of inhibiting the actin rearrangement caused by gliadin and clinical studies have been conducted using this peptide as a therapy for CD.

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This chapter provides a brief overview of current animal models for studying celiac disease, with a focus on generating HLA transgenic mouse models. Human Leukocyte Antigen class II molecules have been a particular target for transgenic mice due to their tight association with celiac disease, and a number of murine models have been developed which had the endogenous MHC class II genes replaced with insertions of disease susceptible HLA class II alleles DQ2 or DQ8. Additionally, transgenic mice that overexpress interleukin-15 (IL-15), a key player in the inflammatory cascade that leads to celiac disease, have also been generated to model a state of chronic inflammation. To explore the contribution of specific bacteria in gluten-sensitive enteropathy, the nude mouse and rat models have been studied in germ-free facilities. These reductionist mouse models allow us to address single factors thought to have crucial roles in celiac disease. No single model has incorporated all of the multiple factors that make up celiac disease. Rather, these mouse models can allow the functional interrogation of specific components of the many stages of, and contributions to, the pathogenic mechanisms that will lead to gluten-dependent enteropathy. Overall, the tools for animal studies in celiac disease are many and varied, and provide ample space for further creativity as well as to characterize the complete and complex pathogenesis of celiac disease.

Self-tolerant T cells can cross-react weakly on self, but are usually incapable of activation. However, when activated these T cells can cross-react effectively on cells expressing self antigens. We have observed that mutants of the MHC class I molecule H2-Kb have structural differences resulting in altered antigen presentation. We hypothesize that structural manipulation of MHC class I can increase stabile amino acid contacts with the TCR. Increasing stabile contacts may decrease the energy barrier required to overcome the threshold for activation, breaking tolerance for self antigens. Using computer modeling techniques, amino acid substitutions at specific sites of MHC class I were predicted to result in stabilization of the TCR:pMHC complex. These altered MHC molecules were made and expressed in cell lines. We have shown that altered MHC enhanced TCR binding. Altered MHC enhanced activation and proliferation of naïve T cells in response to a non-stimulatory, weak antigen. Altered MHC also induced CTL killing against self-antigens. In an in vivo transplant model, protective immunity was induced against a native tumor after an altered MHC expressing tumor challenge. By altering the structure of MHC class I we have activated normally tolerant T cells that are capable of cross-reacting on self.