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?1 (TGF?) 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.

Public Health Relevance

Currently, there are only a handful of medical treatments available for treating the inflammatory bowel diseases (IBD;Crohn's disease;ulcerative colitis) 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. A new and exciting therapy that has shown promise in animal models of chronic inflammatory diseases such as autoimmune encephalomyelitis, allograft rejection, collagen-induced arthritis and graft vs. host disease is treatment with bone marrow-derived mesenchymal stem cells (MSCs). Unfortunately, no attempt has been made to evaluate the therapeutic efficacy of these immune-modifying stem cells in animal models of chronic intestinal inflammation. Because large numbers of MSCs can be grown in the laboratory, we are now in a position to evaluate the therapeutic efficacy of human or mouse MSCs in a well-characterized, mouse model of chronic colitis. In addition to providing a better understanding of how (and where) MSCs to suppress intestinal inflammation, data obtained from the proposed studies may identify new therapeutic strategies that could be used to treat patients with IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK091269-01A1
Application #
8289961
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2012-06-15
Project End
2016-05-31
Budget Start
2012-06-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$327,610
Indirect Cost
$110,110
Name
Texas Tech University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Koboziev, Iurii; Reinoso Webb, Cynthia; Furr, Kathryn L et al. (2014) Role of the enteric microbiota in intestinal homeostasis and inflammation. Free Radic Biol Med 68:122-33