Peripheral and Intestinal Regulatory CD4+CD25high T Cells in Inflammatory Bowel Disease

Maul, Jochen; Loddenkemper, Christoph; Mundt, Pamela; Berg, Erika Gebel; Giese, Thomas; Stallmach, Andreas; Zeitz, Martin; Duchmann, Rainer

doi:10.1053/j.gastro.2005.03.043

Cited by 569 publications

(491 citation statements)

References 34 publications

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“…The ratio between effector T cells and regulatory T (T reg ) cells is markedly increased in patients with IBD 135 . Thus, it is tempting to speculate that increasing T reg cell numbers via T reg cell transfer might restore the bal ance between proinflammatory and anti inflammatory immune cells as a new therapeutic approach in IBD.…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

528

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

528

403

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“…NKT cells are early innate regulatory cells that can suppress autoimmunity . Induction of T reg cells that produce IL-10 and TGF-β are protective for both Th1 and Th2 driven diseases including experimental asthma and IBD Maul et al 2005).…”

Section: Autoimmunity Ibd and Th1 Driven Immune Responsesmentioning

confidence: 99%

The paradoxical effects of vitamin D on type 1 mediated immunity

Cantorna

Bruce

2008

Molecular Aspects of Medicine

122

115

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Low vitamin D status is associated with an increased risk of Th1 mediated autoimmune diseases like inflammatory bowel disease. 1,25(OH) 2 D 3 treatments have been shown to suppress Th1 mediated immunity and protect animals from experimental autoimmunity. Th1 mediated immunity is important for clearance of a number of different infectious diseases. For tuberculosis 1,25(OH) 2 D 3 treatment is associated with decreased Th1 mediated immunity but increased bactericidal activity. Systemic candidiasis is unaffected by 1,25(OH) 2 D 3 treatment. The seemingly paradoxical effects of 1,25(OH) 2 D 3 and vitamin D on Th1 mediated autoimmunity versus infectious immunity point to a broad array of vitamin D targets in the immune system. The interplay of these vitamin D targets and their impact on the host-immune response then dictate the outcome.

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“…Early studies found that patients with CD or UC have decreased numbers of peripheral suppressive CD4 + CD45RO + CD25 + FOXP3 + Treg cells during active disease, suggesting that the severity of disease is inversely correlated with the frequency of peripheral Treg cells. [12][13][14][15] In contrast, several studies have found that the lamina propria, mesenteric lymph nodes and intestinal inflamed mucosa of patients with either CD or UC actually contain increased numbers of Treg cells compared with healthy controls. 5,13,15,16 These data are consistent with findings in other gut-inflammatory conditions, such as diverticulitis, pseudomembranous colitis and cytomegalovirus-induced colitis, which show a similar correlation between an increase in FOXP3 + Treg-cell numbers and disease severity.…”

Section: M M U N O L O G Y R E V I E W a R T I C L Ementioning

confidence: 99%

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

Himmel¹,

Hardenberg²,

Piccirillo³

et al. 2008

Immunology

132

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SummaryTwo related chronic inflammatory diseases, Crohn's disease and ulcerative colitis, are together often referred to as inflammatory bowel disease (IBD). Current treatment options are not curative, and patients face lifelong therapy and debilitation. IBD is thought to be the product of a combination of genetic and environmental factors that result in the abnormal regulation of immune responses. Experimental models have demonstrated that normal CD4 + T-regulatory (Treg) cell responses and commensal bacteria are required for the maintenance of gut immune homeostasis. Recent evidence that CD4 + T cells express Toll-like receptors (TLRs) and respond directly to TLR ligands, suggests that signals from commensal bacteria may directly affect T-cell responses in the gut. In this review, we focus on evidence that defects in Treg cells may underlie IBD in humans. In addition, we discuss evidence that direct signaling via TLRs to T cells can affect IBD and that T-cell-dependent responses to bacterial proteins, such as flagellin, are central to the aetiology of this disease.

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Peripheral and Intestinal Regulatory CD4+CD25high T Cells in Inflammatory Bowel Disease

Cited by 569 publications

References 34 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

The paradoxical effects of vitamin D on type 1 mediated immunity

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

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