The overall goal of this project is to gain further understanding of the mucosal immune system and the defects that contribute to the pathogenesis of human inflammatory bowel disease (IBD). The generation of a number of murine models of IBD has facilitated investigation into the basic mechanisms underlying IBD pathogenesis. Despite the fact that many murine models of IBD result from a defect in a single protein known to affect leukocyte function, the specific auto-reactive and/or regulatory cell population responsible for disease pathogenesis in these models remains unknown. We recently generated a mouse model of IBD that results from the targeted disruption of the Wiskott-Aldrich syndrome protein (WASP). WASP is expressed solely in hematopoietic cells and is a signaling molecule that regulates cell surface receptor signals to the cytoskeleton. Abnormalities in this protein lead to the rare X-linked primary immunodeficiency that carries its name. Autoimmunity is commonly associated with this immunodeficiency, and up to 10 percent of patients develop an IBD-like illness. Our lab has recently shown that 100% of WASP KO (WKO) mice also develop colitis. Genetic and adoptive transfer studies have shown that lymphocytes are essential and CD4+ lymphocytes are sufficient for colitis development. In contrast with most murine models of IBD that have a Th1 bias, we have demonstrated a Th2 cytokine skewing (with elevated IL-4 and IL-13) in lamina propria (LP) lymphocytes and in tissues. Indeed, IL-4 is required, at least in part, for colitis development. Perhaps, most interestingly, we have recently shown that there is marked reduction in the development and function of regulatory T cells in WKO animals. Our overall hypothesis is that the colitis in WKO mice results from both intrinsic Treg dysfunction as well as extrinsic signaling/cytokine abnormalities within the CD4+ T cell/APC population that results in Treg dysfunction. In this proposal we seek to determine the cellular and molecular basis for colitis development and autoimmunity in WKO mice.
Aim 1 seeks to uncover the mechanism(s) (development, migration, and cell-cell contacts) that are responsible for the aberrant Treg development and dysfunction in WKO mice.
Aim 2 seeks to assess the impact of WASP deficiency in innate immune cells on the generation and function of Tregs.
Aim 3 seeks to determine the role of WASP-dependant T cell receptor (TCR) signaling and aberrant cytokine secretion on Treg dysfunction. The overall goal of this proposal is to further our understanding of the mechanism of colitis in WKO mice that is uniquely associated with both profound regulatory T cell defects and Th2 cytokine skewing and to take advantage of a murine model of colitis that uniquely has a human correlate. Our driving premise is that such knowledge will not only aid in the understanding and treatment of the debilitating autoimmunity (and IBD-like illness) that characterizes the human immunodeficiency but will also aid in our understanding of mucosal immune regulation in general and the molecular underpinnings of inflammatory bowel disease.

Public Health Relevance

The overall goal of this proposal is to further our understanding of the regulatory T cell defects and the mechanism of colitis in Wiskott Aldrich Syndrome protein knock-out mice and to take advantage of a model of colitis that also has a human correlate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050950-08
Application #
8415867
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2002-04-05
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
8
Fiscal Year
2013
Total Cost
$323,847
Indirect Cost
$137,728
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Shouval, Dror S; Biswas, Amlan; Goettel, Jeremy A et al. (2014) Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 40:706-19
Nguyen, Deanna D; Muthupalani, Suresh; Goettel, Jeremy A et al. (2013) Colitis and colon cancer in WASP-deficient mice require helicobacter species. Inflamm Bowel Dis 19:2041-50
Ramasamy, Sundaram; Nguyen, Deanna D; Eston, Michelle A et al. (2011) Intestinal alkaline phosphatase has beneficial effects in mouse models of chronic colitis. Inflamm Bowel Dis 17:532-42
Glocker, Erik-Oliver; Kotlarz, Daniel; Boztug, Kaan et al. (2009) Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361:2033-45
Nguyen, Deanna D; Maillard, Michel H; Cotta-de-Almeida, Vinicius et al. (2007) Lymphocyte-dependent and Th2 cytokine-associated colitis in mice deficient in Wiskott-Aldrich syndrome protein. Gastroenterology 133:1188-97
Cotta-de-Almeida, Vinicius; Westerberg, Lisa; Maillard, Michel H et al. (2007) Wiskott Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development. Proc Natl Acad Sci U S A 104:15424-9
Maillard, Michel H; Cotta-de-Almeida, Vinicius; Takeshima, Fuminao et al. (2007) The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J Exp Med 204:381-91
Snapper, Scott B; Meelu, Parool; Nguyen, Deanna et al. (2005) WASP deficiency leads to global defects of directed leukocyte migration in vitro and in vivo. J Leukoc Biol 77:993-8
Cotta-de-Almeida, Vinicius; Schonhoff, Susan; Shibata, Tomoyuki et al. (2003) A new method for rapidly generating gene-targeting vectors by engineering BACs through homologous recombination in bacteria. Genome Res 13:2190-4

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