Regulation of Chronic Colitis by Mesenchymal Stem Cells

Summary

Principal Investigator: Matthew B Grisham
Abstract: DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD;Crohn's disease;ulcerative colitis) are chronic inflammatory disorders of the small bowel and/or colon that affect approximately 1.5 million people in the US with a calculated annual cost for both medical expenses and work loss of almost $4 billion dollars. Currently, there are only a handful of medical treatments available for treating these debilitating inflammatory disorders with only a few new therapies projected to be available in the near future. Thus, there is a clear need for the development of additional therapeutic agents to treat patients with IBD. Although the etiologies of Crohn's disease and ulcerative colitis have yet to be fully elucidated, there is growing clinica and experimental evidence to suggest that chronic gut inflammation results from a dysregulated immune response to commensal enteric antigens. Recent studies demonstrate that bone marrow-derived mesenchymal stem cells (MSCs) have potent immunoregulatory activity in vitro and in vivo. In addition, recent investigations show that the immunosuppressive activity of MSCs in different mouse models of autoimmunity is not restricted to the major histocompatibility complex suggesting that MSCs are "immune-privileged". Several reports demonstrate that adoptive transfer of allogeneic or xenogeneic (human) MSCs successfully engraft in recipient mice or rats where they suppress the inflammation observed in animal models of autoimmune encephalomyelitis, allograft rejection, collagen-induced arthritis and graft vs. host disease. A fe recent studies have reported that mouse or human MSCs attenuate the erosive, self-limiting colitis induced by the oral or rectal administration of toxic chemicals. Although compelling, no attempt has been made to evaluate the therapeutic efficacy of human or mouse MSCs in an animal model of chronic gut inflammation. Therefore, we will evaluate the therapeutic efficacy of human or mouse bone marrow-derived MSCs in a well-characterized, mouse model of chronic colitis. Because MSCs can be grown and expanded in vitro and exert their immunoregulatory activity across major histocompatibility complex barriers in vivo, we are in the unique position to evaluate the therapeutic efficacy of human or mouse MSCs in an animal model that more closely mimics human IBD. We hypothesize that ex vivo-generated MSCs home to the mesenteric lymph nodes (MLNs) and/or colonic lamina propria where they prevent/limit gut inflammation directly via their production of the potent regulatory cytokine TGF[unreadable]1 (TGF[unreadable]) and/or indirectly by inducing the expansion of IL-10-producing regulatory T-cells (Tregs). In order to test this hypothesis we will: a) Evaluate the ability of human or mouse MSCs to suppress the induction of chronic gut inflammation in the presence or absence of MLNs or other secondary lymphoid tissue using mouse models of chronic intestinal inflammation;b) Determine the therapeutic efficacy of human or mouse MSCs in reversing/attenuating preexisting disease in the presence or absence of MLNs or other secondary lymphoid tissue and c) Define the immunoregulatory mechanisms utilized by MSCs to attenuate the induction and perpetuation of chronic gut inflammation. In addition to better understanding the regulatory mechanisms used by MSCs to suppress intestinal inflammation, data obtained from the proposed studies may identify new therapeutic strategies that could be developed to treat patients with IBD.
Funding Period: 2012-06-15 - 2016-05-31
more information: NIH RePORT

Top Publications

  1. pmc Role of the enteric microbiota in intestinal homeostasis and inflammation
    Iurii Koboziev
    Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
    Free Radic Biol Med 68:122-33. 2014

Detail Information

Publications1

  1. pmc Role of the enteric microbiota in intestinal homeostasis and inflammation
    Iurii Koboziev
    Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
    Free Radic Biol Med 68:122-33. 2014
    ..The objective of this review is to present our current understanding of the role that enteric microbiota play in intestinal homeostasis and pathogenesis of chronic intestinal inflammation. ..

Research Grants30

  1. Dendritic Cell Manipulation: A Novel Therapeutic for Inflammatory Bowel Disease
    Jesus Rivera-Nieves; Fiscal Year: 2013
    ..abstract_text> ..
  2. Neuropeptides and Regulatory T cells
    Doina Ganea; Fiscal Year: 2013
    ..The ultimate goal of the present proposal is the development of a combined therapy based on genetically modified tolerogenic dendritic cells, which represents a novel therapeutic approach for the treatment of autoimmune diseases. ..
  3. Intestinal Lymphocyte Trafficking
    Eugene C Butcher; Fiscal Year: 2013
    ....
  4. Enteric Neuronal Development as a Determinant of Intestinal Inflammation
    Kara Gross Margolis; Fiscal Year: 2013
    ..Knowledge of interactions between the ENS and inflammatory effectors, therefore, has the potential to transform understanding and, ultimately, treatment of many intestinal disorders. ..
  5. Targeting CC-Chemokine Receptor 7 for the prevention of graft-versus-host disease
    JAMES M COGHILL; Fiscal Year: 2013
    ..Through these experiences, Dr. Coghill will obtain the skills necessary to transition to an independent, NIH funded laboratory investigator. ..
  6. T CELL RESPONSE TO MYELIN PROTEOLIPID PROTEIN
    Vijay K Kuchroo; Fiscal Year: 2013
    ..Using "reporter" mice for effector and regulatory T cells and autoantigen specific tetramers, we will be able to study the balance and interplay between antigen- specific effector and regulatory T cells during the autoimmune reaction. ..
  7. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013
    ..Such an integrated interdisciplinary approach is possible only through continued support of this PPG. ..
  8. Functional Annotation of the Pancreatic Cancer Genome
    Steven D Leach; Fiscal Year: 2013
    ..Together, these studies will dramatically accelerate the functional annotation of the pancreatic cancer genome, setting the stage for future therapeutic applications. ..
  9. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  10. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  11. Mucosal Immunity, Vaccines and Microbiota Interplay in Humans and Animal
    Marcelo B Sztein; Fiscal Year: 2013
    ..Given the shortcomings of available measures to successfully control this infection, and its bioterrorism potential, to develop a S. dysenteriae type 1 vaccine is of great importance. ..