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Digestive Diseases and Sciences

, Volume 61, Issue 2, pp 423–432 | Cite as

Novel Colitis Immunotherapy Targets Bin1 and Improves Colon Cell Barrier Function

  • Sunil Thomas
  • Joanna M. Mercado
  • James DuHadaway
  • Kate DiGuilio
  • James M. Mullin
  • George C. Prendergast
Original Article

Abstract

Background

Ulcerative colitis (UC) is associated with defects in colonic epithelial barriers as well as inflammation of the colon mucosa resulting from the recruitment of lymphocytes and neutrophils in the lamina propria. Patients afflicted with UC are at increased risk of colorectal cancer. Currently, UC management employs general anti-inflammatory strategies associated with a variety of side effects, including heightened risks of infection, in patients where the therapy is variably effective. Thus, second generation drugs that can more effectively and selectively limit UC are desired.

Aim

Building on genetic evidence that attenuation of the Bin1 (Bridging integrator 1) gene can limit UC pathogenicity in the mouse, we pursued Bin1 targeting as a therapeutic option.

Methods

Mice were injected with a single dose of Bin1 mAb followed by oral administration of 3 % DSS in water for 7 days.

Results

In this study, we offer preclinical proof of concept for a monoclonal antibody (mAb) targeting the Bin1 protein that blunts UC pathogenicity in a mouse model of experimental colitis. Administration of Bin1 mAb reduced colitis morbidity in mice; whereas unprotected mice is characterized by severe lesions throughout the mucosa, rupture of the lymphoid follicle, high-level neutrophil and lymphocyte infiltration into the mucosal and submucosal areas, and loss of surface crypts. In vitro studies in human Caco-2 cells showed that Bin1 antibody altered the expression of tight junction proteins and improved barrier function.

Conclusions

Our results suggest that a therapy based on Bin1 monoclonal antibody supporting mucosal barrier function and protecting integrity of the lymphoid follicle could offer a novel strategy to treat UC and possibly limit risks of colorectal cancer.

Keywords

Inflammatory bowel disease IBD Inflammation Tight junctions Colon cancer 

Notes

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sunil Thomas
    • 1
  • Joanna M. Mercado
    • 1
    • 2
  • James DuHadaway
    • 1
  • Kate DiGuilio
    • 1
    • 2
  • James M. Mullin
    • 1
    • 2
  • George C. Prendergast
    • 1
    • 3
    • 4
  1. 1.Lankenau Institute for Medical ResearchWynnewoodUSA
  2. 2.Division of GastroenterologyLankenau Medical CenterWynnewoodUSA
  3. 3.Department of Pathology, Anatomy and Cell BiologySidney Kimmel Medical SchoolPhiladelphiaUSA
  4. 4.Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA

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