Topics and Potential Rotation Projects:

1) Innate and Adaptive Immune Mechanisms for Regulating Mucosal Inflammation; 2) Characterizing and Manipulating Regulatory T cell Circuits In vivo; 3) Leukocyte and Epithelial Cell Signaling; 4) Regulation of the Actin Cytoskeleton: 5) Host-Microbial Interactions

1) Innate and Adaptive Immune Mechanisms for Regulating Mucosal Inflammation. Recent genetic models of inflammatory disorders of the GI tract have demonstrated: the requirement of bacteria, the involvement of altered T cells with an exaggerated Th1/Th17 response, and the role of disrupted mucosal integrity in the development of disease. We generated WASP KO mice – a model of the human immunodeficiency. These mice develop severe colitis making this model one of only two murine models of inflammatory bowel disease (IBD) that has a human correlate. We have extensively characterized this model and have recently determined that unlike most models of IBD, the colitis in WASP-deficiency is associated with a Th2 cytokine profile. We have also demonstrated that regulatory cells are profoundly defective in vitro and in vivo, and this aberrancy may be responsible for the development of colitis. New data suggest that a defect in antigen presenting cells (APC) may be responsible for the regulatory cell defect in colitis associated with WASP deficiency. We are characterizing the mechanisms underlying the regulatory T cell defect and APC dysfunction - with the goal of determining their unique role in leading to disease development in mice and man.

2) Manipulating Regulatory T cells as a Therapeutic Target in Human IBD. We are establishing a translational mucosal immunology program at MGH with an emphasis on inflammatory disorders of the GI tract. As part of this venture, our laboratory has recently established a new collaboration with the laboratory of Dr. Harold Weiner at BWH with the goal of investigating whether manipulation of regulatory cells in vivo can ameliorate human autoimmune disease. Dr. Weiner's group has recently demonstrated that oral anti-CD3 antibody treatment (which binds a component of the T-cell receptor) can effectively cure murine models of MS, SLE, and diabetes through expansion of TGF-b secreting regulatory cells. In collaboration with his group, we have recently demonstrated that oral anti-CD3 therapy can prevent inflammatory bowel disease in a murine model of IBD. We are assessing the mechanisms responsible for Treg generation and are initiating a phase I/II human trial to assess the effectiveness of oral anti-CD3 therapy in IBD patients.

3) Leukocyte and Epithelial Cell Signaling. We are interested in signaling pathways that regulate lymphoid activation and leukocyte trafficking. We have focused on the WASP (Wiskott-Aldrich syndrome protein) family of proteins that integrate incoming cell surface signals to cytoskeletal changes in leukocytes and epithelial cells. We have demonstrated in vivo and in vitro that WASP-deficient dendritic cells, neutrophils and lymphocytes have marked trafficking abnormalities. Using various approaches, we are further defining hematopoietic signaling pathways regulated by WASP and to elucidate potential defects in cytoskeletal architecture and actin reorganization. We have generated a variety of tissue specific animal models lacking WASP and N-WASP in B cell and T cells to determine the combined role of these proteins in lymphocyte signaling and migration. We have also employed tissue-specific gene targeting approaches to define the role of the more ubiquitously expressed N-WASP in intestinal and skin epithelial function. We have exciting data both in the skin and the GI tract for a role for N-WASP in epithelial function and stem cell homeostasis.