Celiac disease (CeD), a complex T cell-mediated enteropathy induced by dietary gluten in HLA-DQ2 or HLA- DQ8 individuals, currently affects 1% of the global population. While CD4 T cells are required for the development of villus atrophy (VA), the effector cells mediating intestinal epithelial cell destruction (IEC) are intraepithelial cytotoxic lymphocytes (IE-CTLS). Currently, the only effective CeD treatment is a lifelong gluten- free diet (GFD). However, 30-40% of adult CeD patients fail to restore a completely normal intestinal morphology on a GFD, and complete avoidance of gluten can be challenging. During the last funding period, we generated the first HLA and gluten-dependent mouse model of CeD (CeD-tg) that recapitulates the intricacies of CeD pathogenesis. We will take advantage of the CeD-tg mouse model and our expertise in human immunology, to (i) further dissect the mechanisms underlying tissue destruction, and (ii) profile the clinical spectrum of CeD using high dimensional single cell technologies with the goal of identifying new therapeutic avenues and biomarkers predicting tissue destruction. The central hypothesis emerging from our studies is that IE-CTL integrate signals from CD4 T cells and IEC to become licensed killer cells and mediate tissue destruction. Furthermore, while it is acknowledged that IEC play a role in IE-CTL activation, their role in CeD pathogenesis and how they impact on IE-CTL activation has not been investigated. The proposed specific aims are:1) Establish the role of epithelial cells in T cell-mediated CeD immunopathology using the CeD Tg mouse model; 2) Establish the Impact of ?? and CD4 T cells, IFN?, IL-15 on IE-CTL activation in CeD-tg mice; and 3) Profile the heterogeneity of potential and active CeD. The goal is to provide a knowledge base that will help identify appropriate treatment strategies to individual patients, and help predict which potential CeD patients (patients who have develop inflammatory anti-gluten immunity but conserve a normal intestinal architecture) are at high risk of developing VA. The studies proposed will have a significant positive impact on human health because they will help define curative and preventive strategies that have the potential to prevent tissue destruction in celiac disease.
The proposed research will provide a molecular understanding of the mechanisms that control the activation of resident cytolytic T cells that mediate tissue destruction. Furthermore, our study will provide a knowledge base that will help with the interpretation of the outcome of clinical trials and identify appropriate treatment strategies to individual patients. It will have a significant positive impact on human health because it will help define curative and preventive strategies that have the potential to prevent tissue destruction in celiac disease. Thus, this work will directly support the NIDDK mission of developing fundamental knowledge that will help reduce the burden of human disease, and improve the health of patients with digestive disease.
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