Inflammatory pathways in mucosal barrier function during intestinal GvHD

• Applicants: Dr. Wilfried Reichardt; Professor Dr. Robert Zeiser
• Subject Area: Hematology, Oncology
• Term: from 2009 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 91114307

Immune cells can react to tissue injury by recognizing molecules that are normally located inside the cell, but are released upon injury. A molecule with a high intracellular concentration, released upon cell injury is Adenosine-5-triphosphate (ATP). By activation of the NLRP3 inflammasome, ATP can trigger the release of mature IL-1beta. Our previous work has demonstrated a role for the ATP/P2X7 axis for acute graft-versus-host disease (GvHD) (Wilhelm K et al. Nature Medicine 2010). Besides IL-1beta, recent data indicate a role for IL-33, another IL-1 superfamily member, in different models of inflammation. Cells in barrier tissues constitutively express and store IL-33, suggesting its central role in mucosal immunity. Since mucosal immunity is severely dysregulated in acute intestinal GvHD and because we observed that IL-33 is upregulated in dendritic cells (DC) and non-hematopoietic antigen presenting cells that reside in the lamina propria of the inflamed intestinal tract in the early phase of GvHD, this project has the following goals: 1. To delineate signals (lymphopenia, allogeneic MHCs, cytokines) that trigger the expression of the IL-33 receptor ST2 in the Tc and DC compartments. Also we wish to determine the expression and release of IL-33 by colonic myofibroblasts, enterocytes, DCs and fibroblasts. This will be addressed in human and murine tissues with or without GvHD based on the hypothesis that IL-33 may be increasingly expressed and released upon tissue damage. 2. To assess if genetic deficiency of IL-33 or its receptor ST2 in mice have an impact on the severity of acute GvHD, infiltration/activation of allogeneic Tc cells and mucosal barrier integrity. As part of this goal we wish to determine if disruption of mucosal barriers as found in intestinal GvHD can be prevented by blocking ST2. The role of downstream events of ST2 activation including NF-kappa-B and MAPK pathway activity in donor Tc will be studied. 3. To determine the role of miR-146a for GvHD with the prospect of targeting multiple innate inflammatory response pathways simultaneously and tailoring anti-tumor immune responses by blocking miR-146a activity. 4. To quantify transmigration of bacteria through damaged mucosal barriers under different inflammatory conditions with respect to the IL-33/ST2 axis and miR-146a activity by MRT, BLI, PCR, culture and histology. Overall this project aims at determining the role of IL-33 and miR-146a as factors involved in pro- and anti-inflammatory immune responses that impact intestinal mucosal integrity during GvHD.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Jürgen Hennig