Immunoregulation in the gut: success and failures in human disease

Monteleone, Ivan; Vavassori, P.; Biancone, Livia; Monteleone, Giovanni; Pallone, Francesco

doi:10.1136/gut.50.suppl_3.iii60

Cited by 103 publications

(92 citation statements)

References 53 publications

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“…As mentioned, mucosal inflammation in UC has a pattern of cytokine secretion that is similar to the pattern secreted by the Th2 cell-type including increased levels of IL-4, IL-5 and IL-13 [16]. Vice versa IL-4, IL-5 and IL-13 promote Th2 cell differentiation which further may augment levels of IL-13 [16,17]. T-cells can also be directly activated via antigen presentation by APC.…”

Section: Cytokines As Drug Targets In Ibdmentioning

confidence: 97%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

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Significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). A number of susceptibility genes have been detected by large genome wide screening-approaches. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of IBD. TNF blockers have been shown to be very effective for the control of complicated disease courses. Currently, in addition to the three already established anti-TNF antibodies, new anti-TNF molecules, for example Golimumab, are in clinical trials and also reveal promising results. However, not all of the patients respond to anti-TNF treatment and many patients lose their response. Therefore, additional therapeutic approaches are urgently needed. Attractive therapy targets are cytokines as well as their receptors and signaling pathways. At the moment a large number of biologicals and inhibitors are tested in clinical trials and some of them provide very promising results for the treatment of IBD patients. In particular, inhibition of IL-12p40 by specific antibodies as well as of the janus kinase (JAK)3 by a small molecule promise to be very effective approaches. Though antibodies targeting for example IL-6, IL-6R, IL-13 or CCR9 are only in the early steps of clinical development, they have already demonstrated to be a possible treatment option which needs to be confirmed in further trials. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed.

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Section: Cytokines As Drug Targets In Ibdmentioning

confidence: 97%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

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“…S2). Because it is known that both CD and intestinal pathology caused by H. hepaticus are characterized by Th1 dominant chronic inflammation, we next assessed CD4 and CD8 T cells isolated from Peyer's patches and mesenteric lymph nodes for their expression of IFN-γ and IL-4 (35,36). H. hepaticus inoculation resulted in significantly increased IFN-γ producing CD4 and CD8 T cells in both Peyer's patches and mesenteric lymph nodes in Nod2-deficient but not wild-type mice ( Fig.…”

Section: H Hepaticus Induces Th1 Immune Responses In Peyer's Patchesmentioning

confidence: 99%

Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum

Biswas

Liu

Hao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

149

140

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Mutations in the NOD2 gene are strong genetic risk factors for ileal Crohn’s disease. However, the mechanism by which these mutations predispose to intestinal inflammation remains a subject of controversy. We report that Nod2 -deficient mice inoculated with Helicobacter hepaticus , an opportunistic pathogenic bacterium, developed granulomatous inflammation of the ileum, characterized by an increased expression of Th1-related genes and inflammatory cytokines. The Peyer’s patches and mesenteric lymph nodes were markedly enlarged with expansion of IFN-γ–producing CD4 and CD8 T cells. Rip2 -deficient mice exhibited a similar phenotype, suggesting that Nod2 function likely depends on the Rip2 kinase in this model. Transferring wild-type bone marrow cells into irradiated Nod2 -deficient mice did not rescue the phenotype. However, restoring crypt antimicrobial function of Nod2 -deficient mice by transgenic expression of α-defensin in Paneth cells rescued the Th1 inflammatory phenotype. Therefore, through the regulation of intestinal microbes, Nod2 function in nonhematopoietic cells of the small intestinal crypts is critical for protecting mice from a Th1-driven granulomatous inflammation in the ileum. The model may provide insight into Nod2 function relevant to inflammation of ileal Crohn’s disease.

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“…CD is associated with the activation of types 1 and 17 T-helper (Th) cells in response to interleukin (IL)-12, IL-18, IL-23 and transforming growth factor (TGF-), and activation of these cells results in increased secretion of the pro-inflammatory cytokines IL-2, IL-17, interferon (IFN)-and TNF- [8,9]. In patients with UC the mucosal inflammation of the colon is mainly associated with a Th2 cell activation mediated by IL-4, IL-5 and IL-13 that results in an increased level of IL-13 [10,11]. However, in both cases T-cells are also activated by direct contact with antigens [12].…”

Section: Introductionmentioning

confidence: 99%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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Immunoregulation in the gut: success and failures in human disease

Cited by 103 publications

References 53 publications

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

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