Novel Colitis Immunotherapy Targets Bin1 and Improves Colon Cell Barrier Function

Thomas, Sunil; Mercado, Joanna; DuHadaway, James B.; DiGuilio, Kate; Mullin, James M.; Prendergast, George C.

doi:10.1007/s10620-015-3804-8

Cited by 15 publications

(54 citation statements)

References 32 publications

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“…Based on the study we recently demonstrated that treatment of experimental colitis with Bin1 monoclonal antibody would support mucosal barrier function by inducing the expression of TJ proteins thereby protecting the integrity of the lymphoid follicle. The therapy may be a novel strategy to treat UC and possibly limit risks of colorectal cancer (344). Thus lowering Bin1 levels may be a strategy that would lead to enhanced TJ proteins that, in turn, protects against pathogenic microorganisms from crossing the epithelial cells.…”

Section: Microbiome Effects On Intestinal Barrier Function and Inflammentioning

confidence: 99%

The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists

et al. 2017

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Humans consider themselves discrete autonomous organisms, but recent research is rapidly strengthening the appreciation that associated microorganisms make essential contributions to human health and well-being. Each person is inhabited and also surrounded by his/her own signature microbial cloud. A low diversity of microorganisms is associated with a plethora of diseases including allergy, diabetes, obesity, arthritis, inflammatory bowel diseases and even neuropsychiatric disorders. Thus, an interaction of microorganisms with the host immune system is required for a healthy body. Exposure to microorganisms from the moment we are born and appropriate microbiome assembly during childhood are essential for establishing an active immune system necessary to prevent disease later in life. Exposure to microorganisms educates the immune system, induces adaptive immunity and initiates memory B and T cells that are essential to combat various pathogens. The correct microbial-based education of immune cells may be critical in preventing the development of autoimmune diseases and cancer. This review provides a broad overview of the importance of the host microbiome and accumulating knowledge of how it regulates and maintains a healthy human system.

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Section: Microbiome Effects On Intestinal Barrier Function and Inflammentioning

confidence: 99%

The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists

et al. 2017

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“…BIN1 was initially identified in 1996 as a tumor suppressor; subsequently, however, additional functions have been attributed to different protein transcripts. Bin1 is a conserved member of the BAR (Bin‐Amphiphysin‐Rvs) family of adapter proteins implicated in diverse cellular processes including endocytosis, actin organization, programmed cell death, stress responses, and transcriptional control . The BIN1 gene has recently been identified as the most important risk locus for late‐onset Alzheimer's disease, after apolipoprotein E …”

Section: Introductionmentioning

confidence: 99%

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

Thomas

Hoxha

Alexander

et al. 2018

J of Cellular Biochemistry

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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 Cmannitol 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. K E Y W O R D S circadian rhythm, inflammatory bowel disease (IBD), immunotherapy, inflammation, tight junctions, ulcerative colitis (UC), Bin1 monoclonal antibody J Cell Biochem. 2019;120:4225-4237. wileyonlinelibrary.com/journal/jcb | 4225

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“…Under the action of noxious stimulation, the barrier function of intestinal tract could be comprised and lead to disruption of normal physiology. [ 9 , 10 ]…”

Section: Introductionmentioning

confidence: 99%

Effect of Montmorillonite powder on intestinal mucosal barrier in children with abdominal Henoch–Schonlein purpura

et al. 2018

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Background:Our previous studies found that intestinal barrier function has been changed in children with abdominal Henoch–Schonlein purpura (HSP). Montmorillonite has been shown to be protective for digestive tract mucosa.Objective:The present study aimed to investigate whether Montmorillonite powder could improve the intestinal mucosal barrier function in children with abdominal HSP.Methods:Using a randomized controlled study design, we compared plasma levels of diamine oxidase (DAO), d-lactate, and endotoxin in children with abdominal HSP before and after Montmorillonite powder treatment.Results:Among 28 patients in experimental group and 30 in control group, there was no significant difference in age, sex, height, weight, and course of disease between 2 groups (P > .05). Before treatment, there was no statistical difference in DAO, d-lactic acid, and endotoxin between experimental group and the control group (P > .05). However, significant differences were detected for DAO and d-lactate after treatment in comparison to before treatment in the Montmorillonite experimental group (P < .05). Such differences were not found in the control group (P > .05).Conclusion:Montmorillonite powder is effective in the treatment of HSP via maintaining intestinal mucosal barrier function.

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Novel Colitis Immunotherapy Targets Bin1 and Improves Colon Cell Barrier Function

Abstract: 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.

Cited by 15 publications

References 32 publications

The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists

The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists

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

Effect of Montmorillonite powder on intestinal mucosal barrier in children with abdominal Henoch–Schonlein purpura

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