Regional Specialisation of T Cell Subsets and Apoptosis in the Human Gut Mucosa: Differences Between Ileum and Colon in Healthy Intestine and Inflammatory Bowel Diseases

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.

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T-cell-directed therapies in inflammatory bowel diseases

Clinical Science ◽

10.1042/cs20100027 ◽

2010 ◽

Vol 118 (12) ◽

pp. 707-715 ◽

Cited By ~ 31

Author(s):

Giovanni Monteleone ◽

Flavio Caprioli

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Inflammatory Bowel Diseases ◽

Clinical Success ◽

Mucosal Inflammation ◽

Activated T Cells ◽

Cell Accumulation ◽

Bowel Diseases ◽

Inflammatory Bowel

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.

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Disrupted regulatory T cell homeostasis in inflammatory bowel diseases

World Journal of Gastroenterology ◽

10.3748/wjg.v22.i3.974 ◽

2016 ◽

Vol 22 (3) ◽

pp. 974 ◽

Cited By ~ 25

Author(s):

Christophe Pedros

Keyword(s):

T Cell ◽

Inflammatory Bowel Diseases ◽

Regulatory T Cell ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Bowel Diseases ◽

Inflammatory Bowel

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Identification of Disease-associated Traits and Clonotypes in the T Cell Receptor Repertoire of Monozygotic Twins Affected by Inflammatory Bowel Diseases

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz179 ◽

2019 ◽

Vol 14 (6) ◽

pp. 778-790 ◽

Cited By ~ 1

Author(s):

Elisa Rosati ◽

Mikhail V Pogorelyy ◽

C Marie Dowds ◽

Frederik T Moller ◽

Signe B Sorensen ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Inflammatory Bowel Diseases ◽

Intestinal Inflammation ◽

Cell Receptor ◽

Individual Variability ◽

Tcr Repertoire ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Mz Twins

Abstract Background and Aims Intestinal inflammation in inflammatory bowel diseases [IBD] is thought to be T cell mediated and therefore dependent on the interaction between the T cell receptor [TCR] and human leukocyte antigen [HLA] proteins expressed on antigen presenting cells. The collection of all TCRs in one individual, known as the TCR repertoire, is characterised by enormous diversity and inter-individual variability. It was shown that healthy monozygotic [MZ] twins are more similar in their TCR repertoire than unrelated individuals. Therefore MZ twins, concordant or discordant for IBD, may be useful to identify disease-related and non-genetic factors in the TCR repertoire which could potentially be used as disease biomarkers. Methods Employing unique molecular barcoding that can distinguish between polymerase chain reaction [PCR] artefacts and true sequence variation, we performed deep TCRα and TCRβ repertoire profiling of the peripheral blood of 28 MZ twin pairs from Denmark and Germany, 24 of whom were discordant and four concordant for IBD. Results We observed disease- and smoking-associated traits such as sharing, diversity and abundance of specific clonotypes in the TCR repertoire of IBD patients, and particularly in patients with active disease, compared with their healthy twins. Conclusions Our findings identified TCR repertoire features specific for smokers and IBD patients, particularly when signs of disease activity were present. These findings are a first step towards the application of TCR repertoire analyses as a valuable tool to characterise inflammatory bowel diseases and to identify potential biomarkers and true disease causes.

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