Ju, Josephine M.

Abstract 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.

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.