Intestinal barrier tightening by a cell-penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis.

Abstract

Patients afflicted with ulcerative colitis (UC) are at increased risk of colorectal cancer. While its causes are not fully understood, UC is associated with defects in colonic epithelial barriers that sustain inflammation of the colon mucosa caused by recruitment of lymphocytes and neutrophils into the lamina propria. Based on genetic evidence that attenuation of the bridging integrator 1 (Bin1) gene can limit UC pathogenicity in animals, we have explored Bin1 targeting as a therapeutic option. Early feasibility studies in the dextran sodium sulfate mouse model of experimental colitis showed that administration of a cell-penetrating Bin1 monoclonal antibody (Bin1 mAb 99D) could prevent lesion formation in the colon mucosa in part by preventing rupture of lymphoid follicles. In vivo administration of Bin1 mAb altered tight junction protein expression and cecal barrier function. Strikingly, electrophysiology studies in organ cultures showed that Bin1 mAb could elevate resistance and lower 14 C-mannitol leakage across the cecal mucosa, consistent with a direct strengthening of colonic barrier function. Transcriptomic analyses of colitis tissues highlighted altered expression of genes involved in circadian rhythm, lipid metabolism, and inflammation, with a correction of the alterations by Bin1 mAb treatment to patterns characteristic of normal tissues. Overall, our results suggest that Bin1 mAb protects against UC by directly improving colonic epithelial barrier function to limit gene expression and cytokine programs associated with colonic inflammation.

• Authors: Sunil Thomas, Kevther Hoxha, Walker Alexander, John Gilligan, Rima Dilbarova, Kelly Whittaker, Andrew Kossenkov, George C Prendergast, James M Mullin
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 120 Issue 3 Pg. 4225-4237 (03 2019) ISSN: 1097-4644 [Electronic] United States
• PMID: 30269357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibodies, Monoclonal
• Bin1 protein, mouse
• Cytokines
• Nerve Tissue Proteins
• Protective Agents
• Tight Junction Proteins
• Tumor Suppressor Proteins
• Dextran Sulfate

Topics

• Adaptor Proteins, Signal Transducing (immunology)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Caco-2 Cells
• Colitis, Ulcerative (chemically induced, therapy)
• Cytokines (metabolism)
• Dextran Sulfate (pharmacology)
• Disease Models, Animal
• Gene Expression (drug effects)
• Humans
• Immunotherapy (methods)
• Intestinal Mucosa (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Tissue Proteins (immunology)
• Protective Agents (therapeutic use)
• Signal Transduction (drug effects)
• Tight Junction Proteins (metabolism)
• Tight Junctions (drug effects, metabolism)
• Tumor Suppressor Proteins (immunology)