T-cell-directed therapies in inflammatory bowel diseases

Gut inflammation occurring in patients with IBDs (inflammatory bowel diseases) is associated with exaggerated and poorly controlled T-cell-mediated immune responses, which are directed against normal components of the gut flora. T-cells accumulate in the inflamed gut of IBD patients as a result of multiple mechanisms, including enhanced recruitment of cells from the bloodstream, sustained cell cycling and diminished susceptibility of cells to undergo apoptosis. Activated T-cells produce huge amounts of cytokines, which contribute to amplify and sustain the ongoing mucosal inflammation. Strategies aimed at interfering with T-cell accumulation and/or function in the gut have been employed with clinical success in patients with IBDs. In the present article, we review the available results showing that T-cell-directed therapies are useful to dampen the tissue-damaging immune response in IBDs.

Download Full-text

Vedolizumab: Potential Mechanisms of Action for Reducing Pathological Inflammation in Inflammatory Bowel Diseases

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.612830 ◽

2021 ◽

Vol 9 ◽

Author(s):

Matthew Luzentales-Simpson ◽

Yvonne C. F. Pang ◽

Ada Zhang ◽

James A. Sousa ◽

Laura M. Sly

Keyword(s):

T Cells ◽

T Cell ◽

Inflammatory Bowel Diseases ◽

Necrosis Factor Alpha ◽

Cell Recruitment ◽

Inflammatory Monocytes ◽

Increased Risk ◽

Bowel Diseases ◽

Cytokine Tumor Necrosis Factor ◽

Inflammatory Bowel

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), and Crohn’s disease (CD), are a group of disorders characterized by chronic, relapsing, and remitting, or progressive inflammation along the gastrointestinal tract. IBD is accompanied by massive infiltration of circulating leukocytes into the intestinal mucosa. Leukocytes such as neutrophils, monocytes, and T-cells are recruited to the affected site, exacerbating inflammation and causing tissue damage. Current treatments used to block inflammation in IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologics. The first successful biologic, which revolutionized IBD treatment, targeted the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Infliximab, adalimumab, and other anti-TNF antibodies neutralize TNFα, preventing interactions with its receptors and reducing the inflammatory response. However, up to 40% of people with IBD become unresponsive to anti-TNFα therapy. Thus, more recent biologics have been designed to block leukocyte trafficking to the inflamed intestine by targeting integrins and adhesins. For example, natalizumab targets the α4 chain of integrin heterodimers, α4β1 and α4β7, on leukocytes. However, binding of α4β1 is associated with increased risk for developing progressive multifocal leukoencephalopathy, an often-fatal disease, and thus, it is not used to treat IBD. To target leukocyte infiltration without this life-threatening complication, vedolizumab was developed. Vedolizumab specifically targets the α4β7 integrin and was approved to treat IBD based on the presumption that it would block T-cell recruitment to the intestine. Though vedolizumab is an effective treatment for IBD, some studies suggest that it may not block T-cell recruitment to the intestine and its mechanism(s) of action remain unclear. Vedolizumab may reduce inflammation by blocking recruitment of T-cells, or pro-inflammatory monocytes and dendritic cells to the intestine, and/or vedolizumab may lead to changes in the programming of innate and acquired immune cells dampening down inflammation.

Download Full-text

Gut microbiota induce local and systemic CD4 T cell responses in healthy individuals that are altered in inflammatory bowel diseases

10.1055/s-0037-1604874 ◽

2017 ◽

Author(s):

AN Hegazy ◽

N West ◽

MJT Stubbington ◽

E Wendt ◽

K Suijker ◽

...

Keyword(s):

T Cell ◽

Gut Microbiota ◽

Inflammatory Bowel Diseases ◽

T Cell Responses ◽

Cd4 T Cell ◽

Healthy Individuals ◽

Cell Responses ◽

Bowel Diseases ◽

Inflammatory Bowel

Download Full-text

Cytomegalovirus and Inflammatory Bowel Diseases (IBD) with a Special Focus on the Link with Ulcerative Colitis (UC)

Microorganisms ◽

10.3390/microorganisms8071078 ◽

2020 ◽

Vol 8 (7) ◽

pp. 1078

Author(s):

Alexandre Jentzer ◽

Pauline Veyrard ◽

Xavier Roblin ◽

Pierre Saint-Sardos ◽

Nicolas Rochereau ◽

...

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Diseases ◽

Viral Reactivation ◽

Steroid Resistance ◽

Mucosal Inflammation ◽

Special Focus ◽

Close Relationship ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Cmv Colitis

Cytomegalovirus (CMV) infects approximately 40% of adults in France and persists lifelong as a latent agent in different organs, including gut. A close relationship is observed between inflammation that favors viral expression and viral replication that exacerbates inflammation. In this context, CMV colitis may impact the prognosis of patients suffering from inflammatory bowel diseases (IBDs), and notably those with ulcerative colitis (UC). In UC, the mucosal inflammation and T helper cell (TH) 2 cytokines, together with immunomodulatory drugs used for controlling flare-ups, favor viral reactivation within the gut, which, in turn, increases mucosal inflammation, impairs corticoid and immunosuppressor efficacy (the probability of steroid resistance is multiplied by more than 20 in the case of CMV colitis), and enhances the risk for colectomy. This review emphasizes the virological tools that are recommended for exploring CMV colitis during inflammatory bowel diseases (IBD) and underlines the interest of using ganciclovir for treating flare-ups associated to CMV colitis in UC patients.

Download Full-text

Microbiota-independent immunological effects of non-digestible oligosaccharides in the context of inflammatory bowel diseases

Proceedings of The Nutrition Society ◽

10.1017/s0029665120006953 ◽

2020 ◽

Vol 79 (4) ◽

pp. 468-478 ◽

Cited By ~ 1

Author(s):

Stefania Del Fabbro ◽

Philip C. Calder ◽

Caroline E. Childs

Keyword(s):

Inflammatory Bowel Diseases ◽

Immune Cell ◽

Intestinal Inflammation ◽

Mechanisms Of Action ◽

Mucosal Inflammation ◽

Disease States ◽

Inflammatory Conditions ◽

Bowel Diseases ◽

Inflammatory Bowel

The aim of the present paper is to review the effects of non-digestible oligosaccharides (NDO) on immunity, focusing on their microbiota-independent mechanisms of action, as well as to explore their potential beneficial role in inflammatory bowel diseases (IBD). IBD are chronic, inflammatory conditions of the gastrointestinal tract. Individuals with IBD have an aberrant immune response to commensal microbiota, resulting in extensive mucosal inflammation and increased intestinal permeability. NDO are prebiotic fibres well known for their role in supporting intestinal health through modulation of the gut microbiota. NDO reach the colon intact and are fermented by commensal bacteria, resulting in the production of SCFA with immunomodulatory properties. In disease states characterised by increased gut permeability, prebiotics may also bypass the gut barrier and directly interact with intestinal and systemic immune cells, as demonstrated in patients with IBD and in infants with an immature gut. In vitro models show that fructooligosaccharides, inulin and galactooligosaccharides exert microbiota-independent effects on immunity by binding to toll-like receptors on monocytes, macrophages and intestinal epithelial cells and by modulating cytokine production and immune cell maturation. Moreover, animal models and human supplementation studies demonstrate that some prebiotics, including inulin and lactulose, might reduce intestinal inflammation and IBD symptoms. Although there are convincing preliminary data to support NDO as immunomodulators in the management of IBD, their mechanisms of action are still unclear and larger standardised studies need to be performed using a wider range of prebiotics.

Download Full-text

Protective Effects of ALDH1A Enzyme Inhibition on Helicobacter-Induced Colitis in Smad3−/− Mice are Associated with Altered α4ß7 Integrin Expression on Activated T Cells

Nutrients ◽

10.3390/nu12102927 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2927

Author(s):

Audrey Seamons ◽

Michael Haenisch ◽

Stacey Meeker ◽

Olesya Pershutkina ◽

Thea Brabb ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Enzyme Inhibition ◽

Treatment Options ◽

T Cell Subsets ◽

Protective Effects ◽

Activated T Cells ◽

Before And After ◽

Inflammatory Bowel ◽

Draining Lymph Nodes

Many inflammatory bowel disease (IBD) patients require surgical intervention due to limited pharmacological treatment options. Antibodies targeting α4ß7, a gut-homing integrin, are one of the most promising IBD treatments. As retinoic acid (RA) regulates expression of gut-homing proteins including α4ß7 integrin, we tested if ALDH1A enzymes in the RA synthesis pathway could be targeted for IBD treatment using a potent inhibitor, WIN 18,446. Age- and sex-matched Smad3−/− mice were fed a diet with and without WIN 18,446 for 3 weeks before triggering inflammation with Helicobacter bilis infection. Colitis was evaluated by histopathology one week following the IBD trigger, and T cell subsets were evaluated before and after the IBD trigger. WIN 18,446 treatment significantly reduced IBD severity in Smad3−/− mice and reduced expression of α4ß7 integrin on multiple activated CD4+ T cell subsets. This change was associated with increased ratios of induced regulatory T cells to Th17 cells during the inflammatory response in the draining lymph nodes. These studies indicate that RA reduction via ALDH1A enzyme inhibition is a potential new target for IBD treatment. Further studies are needed to examine its effects on other types of immune cells, to evaluate the efficacy window for this target, and to determine its efficacy in other animal models of IBD.

Download Full-text

Protective effects of a novel probiotic strain, Lactococcus lactis ML2018, in colitis: in vivo and in vitro evidence

Food & Function ◽

10.1039/c8fo02301h ◽

2019 ◽

Vol 10 (2) ◽

pp. 1132-1145 ◽

Cited By ~ 12

Author(s):

Meiling Liu ◽

Xiuxia Zhang ◽

Yunpeng Hao ◽

Jinhua Ding ◽

Jing Shen ◽

...

Keyword(s):

Immune Responses ◽

Lactococcus Lactis ◽

Intestinal Microbiota ◽

Inflammatory Bowel Diseases ◽

Probiotic Strain ◽

Protective Effects ◽

Bowel Diseases ◽

Inflammatory Bowel

Multiple articles have confirmed that an imbalance of the intestinal microbiota is closely related to aberrant immune responses of the intestines and to the pathogenesis of inflammatory bowel diseases (IBDs).

Download Full-text

Role of Exosomes in the Regulation of T-cell Mediated Immune Responses and in Autoimmune Disease

Cells ◽

10.3390/cells8020154 ◽

2019 ◽

Vol 8 (2) ◽

pp. 154 ◽

Cited By ~ 34

Author(s):

Alberto Anel ◽

Ana Gallego-Lleyda ◽

Diego de Miguel ◽

Javier Naval ◽

Luis Martínez-Lostao

Keyword(s):

T Cells ◽

T Cell ◽

Autoimmune Disease ◽

Immune Responses ◽

T Regulatory Cells ◽

Inflammatory Diseases ◽

Activated T Cells ◽

Regulatory Processes ◽

Activation Induced Cell Death

: T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention or development of autoimmune disease. The expression of membrane-bound death ligands on the surface of exosomes during AICD or the more recently described transfer of miRNA or even DNA inside T-cell exosomes is a molecular mechanism that will be analyzed.

Download Full-text

IRF5 Acts as a Potential Therapeutic Marker in Inflammatory Bowel Diseases

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa200 ◽

2020 ◽

Author(s):

Yonghong Yang ◽

Cui Zhang ◽

Dehuai Jing ◽

Heng He ◽

Xiaoyu Li ◽

...

Keyword(s):

T Cells ◽

Disease Activity ◽

Inflammatory Bowel Diseases ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Mononuclear Cells ◽

Orphan Receptor ◽

Peripheral Blood Mononuclear ◽

Bowel Diseases ◽

Inflammatory Bowel

Abstract Background Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic inflammatory disorders. As is well known, interferon regulatory factor (IRF) 5 is closely associated with the pathogenesis of various inflammatory diseases. But the exact role of IRF5 in IBD remains unclear. Methods In this study, we detected IRF5 expression in peripheral blood mononuclear cells (PBMCs) and inflamed mucosa from IBD patients by immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction. Peripheral blood CD4+ T cells were stimulated with inflammatory cytokines and transfected by lentivirus. Results In active IBD patients, the expression of IRF5 in PBMCs and inflamed colonic tissues was obviously increased and significantly associated with disease activity. Ectopic overexpression of IRF5 could promote the differentiation of IBD CD4+ T cells into Th1 and Th17 cells by regulating T-bet and RAR related orphan receptor C, whereas knockdown of IRF5 had the opposite effects. Tumor necrosis factor (TNF)-α upregulated expression of IRF5 in CD4+ T cells, but anti-TNF treatment with infliximab could markedly reduce IRF5 expression in CD4+ T cells and intestinal mucosa of CD patients. Conclusion Our study reveals a novel mechanism that IRF5 levels are correlated with disease activity in IBD and might function as a possible marker for the management of IBD via regulating Th1 and Th17 immune responses and cytokine production.

Download Full-text