[R01] Longitudinal analysis of T-B cell interactions and clonal dynamics to identify immune programs controlling tissue damage and healing in celiac disease

Ente: National Institute of Diabetes and Digestive and Kidney Diseases

Scadenza: 2030-06-30

Importo max: $819,998

Paese: US

Descrizione

PROJECT SUMMARY/ABSTRACT Celiac disease (CeD) is an autoimmune-like small intestinal enteropathy induced by dietary gluten in genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules. There is a spectrum in tissue damage with potential CeD patients developing inflammatory anti-gluten T cell immunity in the absence of tissue damage, while active CeD is associated with tissue damage ranging from partial to total villous atrophy. Gluten-free diet (GFD) is to this date the only treatment for CeD. However, 50% of CeD patients are unable to effectively adhere to a diet that sustainably excludes gluten, suffering therefore from inadvertent gluten exposure. Moreover, more than 30% of CeD patients have persistent high symptom burdens, resulting from continued mucosal damage despite adhering to a GFD. Persistent mucosal injury on a GFD is associated with several severe complications, including lymphoproliferative malignancy and bone diseases. Although much progress has been made in understanding the immunopathogenesis of CeD, biologic mechanisms underlying interindividual differences in clinical presentations and capacity to heal on a GFD are unknown. Qualitative and/or quantitative differences in the pool of pathogenic lymphocytes accumulating in the intestinal tissue could explain this heterogeneity. Despite mounting evidence from in vitro and murine models that a crosstalk between T cells, B cells, and plasma cells plays a critical role to increase the gluten-specific T cell response to a pathogenic threshold, whether T cell-B cell and T cell-plasma cell interactions contribute to enhancing the local T cell-mediated immune responses that have a direct impact on the formation of the gut celiac lesion has not been studied in humans. In addition, whether an altered mucosal suppressive CD4+ T cell response to gluten contributes to CeD pathogenesis is also unknown. The central hypothesis of this grant proposal is that pathogenic T cell clones responsible for the persistence of the gut celiac lesion and the inability of the tissue to heal are maintained through interactions with B cells and/or plasma cells or because of the inability of regulatory T cells to exert their suppressive function. Multiplex imaging and spatial transcriptomics coupled with B cell and T cell receptors repertoire analysis will be at the core of this proposal to determine lymphocyte clonal dynamics as well as cellular neighborhoods and spatial compartmentalization that support cellular interactions and their impact on tissue remodeling. Istituzione: UNIVERSITY OF CHICAGO PI: Valerie Abadie Progetto: 1R01DK145044-01A1

Settori: National Institute of Diabetes and Digestive and Kidney Diseases

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