Skip to main content

Advertisement

Log in

Novel Colitis Immunotherapy Targets Bin1 and Improves Colon Cell Barrier Function

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365:1713–1725.

    Article  CAS  PubMed  Google Scholar 

  2. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–535.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Das P, Goswami P, Das TK, et al. Comparative tight junction protein expressions in colonic Crohn’s disease, ulcerative colitis, and tuberculosis: a new perspective. Virchows Arch. 2012;460:261–270.

    Article  CAS  PubMed  Google Scholar 

  4. Su L, Shen L, Clayburgh DR, et al. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology. 2009;136:551–563.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Madara JL. Regulation of the movement of solutes across tight junctions. Ann Rev Physiol. 1998;60:143–159.

    Article  CAS  Google Scholar 

  6. Yapal S. Anti-TNF treatment in inflammatory bowel disease. Ann Gastroenterol. 2007;20:48–53.

    Google Scholar 

  7. Prendergast GC, Muller AJ, Ramalingam A, Chang MY. BAR the door: cancer suppression by amphiphysin-like genes. Biochim Biophys Acta. 2009;1795:25–36.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Chang MYBJ, Valenzano MC, Soler AP, Muller AJ, Mullin JM, Prendergast GC. Bin1 attenuation suppresses experimental colitis by enforcing intestinal barrier function. Dig Dis Sci. 2012;57:1813–1821.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. DuHadaway JB, Lynch FJ, Brisbay S, et al. Immunohistochemical analysis of Bin1/Amphiphysin II in human tissues: diverse sites of nuclear expression and losses in prostate cancer. J Cell Biochem. 2003;88:635–642.

    Article  CAS  PubMed  Google Scholar 

  10. Peterson MD, Mooseker MS. Characterization of the enterocyte-like brush border cytoskeleton of the C2BBe clones of the human intestinal cell line, Caco-2. J Cell Sci. 1992;102:581–600.

    CAS  PubMed  Google Scholar 

  11. Wang X, Valenzano MC, Mercado JM, Zurbach EP, Mullin JM. Zinc supplementation modifies tight junctions and alters barrier function of CACO-2 human intestinal epithelial layers. Dig Dis Sci. 2013;58:77–87.

    Article  PubMed  Google Scholar 

  12. Kowalik S, Clauss W, Zahner H. Toxoplasma gondii: changes of transepithelial ion transport in infected HT29/B6 cell monolayers. Parasitol Res. 2004;92:152–158.

    Article  PubMed  Google Scholar 

  13. Metz R, Duhadaway JB, Rust S, et al. Zinc protoporphyrin IX stimulates tumor immunity by disrupting the immunosuppressive enzyme indoleamine 2,3-dioxygenase. Mol Cancer Ther. 2010;9:1864–1871.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Mullin JM, Marano CW, Laughlin KV, Nuciglio M, Stevenson BR, Soler P. Different size limitations for increased transepithelial paracellular solute flux across phorbol ester and tumor necrosis factor-treated epithelial cell sheets. J Cell Physiol. 1997;171:226–233.

    Article  CAS  PubMed  Google Scholar 

  15. Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology. 1995;109:1344–1367.

    Article  CAS  PubMed  Google Scholar 

  16. Egger B, Bajaj-Elliott M, MacDonald TT, Inglin R, Eysselein VE, Buchler MW. Characterisation of acute murine dextran sodium sulphate colitis: cytokine profile and dose dependency. Digestion. 2000;62:240–248.

    Article  CAS  PubMed  Google Scholar 

  17. Basler MDM, Moll C, Groettrup M, Kirk CJ. Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J Immunol. 2010;185:634–641.

    Article  CAS  PubMed  Google Scholar 

  18. Kwon HS, Oh SM, Kim JK. Glabridin, a functional compound of liquorice, attenuates colonic inflammation in mice with dextran sulphate sodium-induced colitis. Clin Exp Immunol. 2008;151:165–173.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Shen L, Su L, Turner JR. Mechanisms and functional implications of intestinal barrier defects. Dig Dis. 2009;27:443–449.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Van Itallie CM, Anderson JM. Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol. 2014;36c:157–165.

    Article  Google Scholar 

  21. Amasheh SMN, Gitter AH, Schöneberg T, Mankertz J, Schulzke JD, Fromm M. Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci. 2002;115:4969–4976.

    Article  CAS  PubMed  Google Scholar 

  22. Masuda H, Iwai S, Tanaka T, Hayakawa S. Expression of IL-8, TNF-alpha and IFN-gamma m-RNA in ulcerative colitis, particularly in patients with inactive phase. J Clin Lab Immunol. 1995;46:111–123.

    CAS  PubMed  Google Scholar 

  23. Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in immune suppression and cancer. Curr Cancer Drug Targets. 2007;7:31–40.

    Article  CAS  PubMed  Google Scholar 

  24. Prendergast GC, Metz R, Muller AJ. Towards a genetic definition of cancer-associated inflammation: role of the IDO pathway. Am J Pathol. 2010;176:2082–2087.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005;11:312–319.

    Article  CAS  PubMed  Google Scholar 

  26. Chapuis JHF, Gistelinck M, Mounier A, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013;18:1225–1234.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Kingwell K. Alzheimer disease: BIN1 variant increases risk of Alzheimer disease through tau. Nat Rev Neurol. 2013;9:184.

    Article  PubMed  Google Scholar 

  28. De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC. Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014;17:1156–1163.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Chang MYBJ, Katz JB, Wang L, et al. Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer. Cancer Res. 2007;67:7605–7612.

    Article  CAS  PubMed  Google Scholar 

  30. Kamel OW. Unraveling the mystery of the lymphoid follicle. Am J Pathol. 1999;155:681–682.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Arimura Y, Nagaishi K, Hosokawa M. Dynamics of claudins expression in colitis and colitis-associated cancer in rat. Methods Mol Biol. 2011;762:409–425.

    Article  CAS  PubMed  Google Scholar 

  32. Hering NA, Fromm M, Schulzke JD. Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics. J Physiol. 2012;590:1035–1044.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Oshima T, Miwa H, Joh T. Changes in the expression of claudins in active ulcerative colitis. J Gastroenterol Hepatol. 2008;23:S146–S150.

    Article  CAS  PubMed  Google Scholar 

  34. Ahmad RCR, Olivares-Villagómez D, Habib T, et al. Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal Immunol. 2014;7:1340–1353.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sunil Thomas.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thomas, S., Mercado, J.M., DuHadaway, J. et al. Novel Colitis Immunotherapy Targets Bin1 and Improves Colon Cell Barrier Function. Dig Dis Sci 61, 423–432 (2016). https://doi.org/10.1007/s10620-015-3804-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-015-3804-8

Keywords

Navigation