Tissue damage in Ulcerative colitis (UC) is predominantly ulceration of the epithelium and its underlying basement membrane. In contrast, Crohn's disease (CD) is characterized by excessive deposition of fibrillar collagen in the lamina propria, muscularis mucosa, submucosa, muscularis propria, and serosa. Thus, in both forms of inflammatory bowel disease (IBD) tissue remodeling and the destruction and restitution of the interstitium are continual and dynamic processes that contribute to anatomical destruction and major clinical consequences. In that mucosal T lymphocytes are enmeshed in the complex and highly organized network of proteins, glycoproteins, and proteoglycans known as the extracellular matrix (ECM), we propose that the chronicity, exacerbation, and recurrence of IBD are multifactorial, involving a process by which the intermingled pathogenic T cells adversely affects tissue injury and fibrosis, and vice versa. Our published and preliminary results show that integrin-mediated adhesion to the ECM is a central event in the generation of an immune response. Therefore, we postulate that ECM adhesion and accessory function is also a pivotal mechanism that modulates IBD. We report that the signal transduction pathway initiated by collagen in an effector/memory T cell is different from that initiated by fibronectin. In addition, the Rho family member of small GTPases, which regulate cytoskeletal reorganization, activated in a T cell adherent to fibronectin differs from that activated when the T cell is bound to collagen, and that the pattern of serine phosphorylation on the head domain of vimentin (the key component of the intermediate filament in T cells) is similarly distinct. We also demonstrate that a three dimensional, native ECM synthesized by human intestinal fibroblasts (HIF) from a control patient initiates a signal transduction cascade in T cells different from that initiated by a native matrix secreted by HIF from patients with Crohn's disease. When we couple the observation that (i) CD-derived native ECM mimics the transduction cascade initiated by purified collagen to (ii) the excessive deposition of collagen in the chronically inflamed CD mucosa and lamina propria, we propose the following central hypothesis: During the continuous remodeling of the ECM in IBD, a repair process quite distinct between UC and CD, engagement of select integrins on mucosal T cells modulates and potentially disrupts their signaling and function, thus contributing to chronicity and recurrence of the inflammatory process. This hypothesis will be tested by two specific aims:
Aim 1. Molecular: Define the signaling pathways engaged by alternate ECM receptors that regulate LPT cytoskeletal rearrangement with a particular focus on the Rho family of small GTPases.
Aim 2. Biochemical: Evaluate the specific protein serine kinases and target proteins modulated by the ligation of distinct integrin molecules in the migratory LPT, with a particular focus on vimentin.

Public Health Relevance

To protect us from infections we have a complex system of white blood cells, the leader of these is called the T lymphocyte, which makes strategic decisions for host defense. T cells isolated from the colon or small bowel normally respond very weakly when compared to T cells isolated from blood, and T cells isolated from inflamed intestinal areas in patients with the inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease, respond with still yet another distinct character. A network, known as the extracellular matrix (ECM), that holds tissue together has been overlooked as a possible T cell regulator, despite its critical role in the side effect of fibrosis in these diseases. This proposal will characterize the ability of each component of the ECM to individually modulate T cell function, morphology, and migration. Knowledge about unique features in ulcerative colitis- or Crohn's disease-derived T cells will enable us to design new therapies for these crippling diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Meisch, Jeffrey P; Nishimura, Michiko; Vogel, Ryan M et al. (2013) Human ?-defensin 3 peptide is increased and redistributed in Crohn's ileitis. Inflamm Bowel Dis 19:942-53
Glick, Abigail B; Wodzinski, Alaina; Fu, Pingfu et al. (2013) Impairment of regulatory T-cell function in autoimmune thyroid disease. Thyroid 23:871-8
Meisch, Jeffrey P; Vogel, Ryan M; Schlatzer, Daniela M et al. (2013) Human ?-defensin 3 induces STAT1 phosphorylation, tyrosine phosphatase activity, and cytokine synthesis in T cells. J Leukoc Biol 94:459-71
Goodman, Wendy A; Young, Andrew B; McCormick, Thomas S et al. (2011) Stat3 phosphorylation mediates resistance of primary human T cells to regulatory T cell suppression. J Immunol 186:3336-45
Stubblefield Park, Samantha R; Widness, Mi; Levine, Alan D et al. (2011) T cell-, interleukin-12-, and gamma interferon-driven viral clearance in measles virus-infected brain tissue. J Virol 85:3664-76
Mandal, Debasmita; Levine, Alan D (2010) Elevated IL-13Ralpha2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway. Inflamm Bowel Dis 16:753-64
Mandal, Debasmita; Fu, Pingfu; Levine, Alan D (2010) REDOX regulation of IL-13 signaling in intestinal epithelial cells: usage of alternate pathways mediates distinct gene expression patterns. Cell Signal 22:1485-94
Franko, Jennifer L; Levine, Alan D (2009) Antigen-independent adhesion and cell spreading by inducible costimulator engagement inhibits T cell migration in a PI-3K-dependent manner. J Leukoc Biol 85:526-38
Das, Lopamudra; Levine, Alan D (2008) TGF-beta inhibits IL-2 production and promotes cell cycle arrest in TCR-activated effector/memory T cells in the presence of sustained TCR signal transduction. J Immunol 180:1490-8
Kugathasan, S; Saubermann, L J; Smith, L et al. (2007) Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut 56:1696-705

Showing the most recent 10 out of 19 publications