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



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.


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.


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


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.


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.


Inflammatory bowel disease IBD Inflammation Tight junctions Colon cancer 


Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365:1713–1725.CrossRefPubMedGoogle Scholar
  2. 2.
    Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–535.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Madara JL. Regulation of the movement of solutes across tight junctions. Ann Rev Physiol. 1998;60:143–159.CrossRefGoogle Scholar
  6. 6.
    Yapal S. Anti-TNF treatment in inflammatory bowel disease. Ann Gastroenterol. 2007;20:48–53.Google Scholar
  7. 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.PubMedCentralPubMedGoogle Scholar
  8. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 15.
    Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology. 1995;109:1344–1367.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Shen L, Su L, Turner JR. Mechanisms and functional implications of intestinal barrier defects. Dig Dis. 2009;27:443–449.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Van Itallie CM, Anderson JM. Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol. 2014;36c:157–165.CrossRefGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 23.
    Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in immune suppression and cancer. Curr Cancer Drug Targets. 2007;7:31–40.CrossRefPubMedGoogle Scholar
  24. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Kingwell K. Alzheimer disease: BIN1 variant increases risk of Alzheimer disease through tau. Nat Rev Neurol. 2013;9:184.CrossRefPubMedGoogle Scholar
  28. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 30.
    Kamel OW. Unraveling the mystery of the lymphoid follicle. Am J Pathol. 1999;155:681–682.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Oshima T, Miwa H, Joh T. Changes in the expression of claudins in active ulcerative colitis. J Gastroenterol Hepatol. 2008;23:S146–S150.CrossRefPubMedGoogle Scholar
  34. 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.PubMedCentralCrossRefPubMedGoogle Scholar

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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