The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children

Mutalib, Mohamed; Borrelli, Osvaldo; Blackstock, Sarah; Kiparissi, F.; Elawad, Mamoun; Shah, Neil; Lindley, Keith

doi:10.1016/j.crohns.2014.08.014

Cited by 64 publications

(50 citation statements)

References 24 publications

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“…It was reported that after the application of sirolimus, 45% UC patients and 100% CD patients reached the clinical stable stage. Meanwhile, sirolimus contributes to the promotion of intestinal mucus restoration (178). In addition, after the occurrence of the spontaneous colitis in IL-10-deficient mice, researchers found out that treating with everolimus for 4 weeks significantly reduced the disease activity index as well as the infiltration of lymphocytes in spleen, mesenteric lymph nodes, and inherent layer (179).…”

Section: Pharmacological Intervention Of Autophagy In the Treatment Omentioning

confidence: 99%

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

Peng

Shao

et al. 2017

Front. Immunol.

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Intestinal mucosal barrier, mainly composed of the intestinal mucus layer and the epithelium, plays a critical role in nutrient absorption as well as protection from pathogenic microorganisms. It is widely acknowledged that the damage of intestinal mucosal barrier or the disturbance of microorganism balance in the intestinal tract contributes greatly to the pathogenesis and progression of inflammatory bowel disease (IBD), which mainly includes Crohn’s disease and ulcerative colitis. Autophagy is an evolutionarily conserved catabolic process that involves degradation of protein aggregates and damaged organelles for recycling. The roles of autophagy in the pathogenesis and progression of IBD have been increasingly studied. This present review mainly describes the roles of autophagy of Paneth cells, macrophages, and goblet cells in IBD, and finally, several potential therapeutic strategies for IBD taking advantage of autophagy.

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Section: Pharmacological Intervention Of Autophagy In the Treatment Omentioning

confidence: 99%

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

Peng

Shao

et al. 2017

Front. Immunol.

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“…Next, to determine a mechanism to limit TNBS fibrosis we evaluated the effects of rapamycin, a pharmacological inhibitor of mTOR activity 15,16 . Accordingly, we treated mice with both TNBS and rapamycin and analyzed αSMA and collagen level in colon histology and have shown quantitative measurement of αSMA and collagen in densitometry plot (Figure 3A).…”

Section: Representative Resultsmentioning

confidence: 99%

Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin

Mathur

Alam

Zhao

et al. 2019

JoVE

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Significant studies have been carried out to understand effective management of intestinal fibrosis. However, the lack of better knowledge of fibrosis has hindered the development of a preventative drug. Primarily, finding a suitable animal model is challenging in understanding the mechanism of Crohn's-associated intestinal fibrosis pathology. Here, we adopted an effective method where TNBS chemical exposure to mice rectums produces substantially deep ulceration and chronic inflammation, and the mice then chronically develop intestinal fibrosis. Also, we describe a technique where a rapamycin injection shows inhibitory effects on TNBS-mediated fibrosis in the mouse model. To assess the underlying mechanism of fibrosis, we methodically discuss a procedure for purifying Cx3Cr1+ cells from the lamina propria of TNBS-treated and control mice. This detailed protocol will be helpful to researchers who are investigating the mechanism of fibrosis and pave the path to find a better therapeutic invention for Crohn's-associated intestinal fibrosis.

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“…Studies involving mouse models have shown that rapamycin (sirolimus), which upregulates autophagy by inhibiting mTOR, can ameliorate experimental colitis . A beneficial effect of sirolimus has also been reported in a case study of an adult with refractory CD and a retrospective case series of children with refractory IBD, although no randomised placebo‐controlled trials have yet been performed. This, however, remains an active area of research, not least because sirolimus is also known to also have anti‐fibrotic effects that could be beneficial in CD – a trial investigating this is currently underway (NCT02675153).…”

Section: Unravelling Disease Pathogenesis – the Genetic Contributionmentioning

confidence: 99%

Genome‐wide association studies in Crohn's disease: Past, present and future

2018

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Over the course of the past decade, genome‐wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL‐17/IL‐23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development – a realisation that is now being incorporated into the design of new treatments. However, despite these successes, a significant proportion of disease heritability remains unexplained. Similarly, most of the causal variants at associated loci have not yet been identified, and even fewer have been functionally characterised. Because of the inarguable rise in the incidence of CD in regions of the world that previously had low disease rates, GWAS studies will soon have to shift from a largely Caucasian focus to include populations from other ethnic backgrounds. Future studies should also move beyond conventional studies of disease susceptibility into phenotypically driven ‘within‐cases’ analyses in order to explore the role of genetics in other important aspects of disease biology. These studies are likely to include assessments of prognosis and/or response to treatments and may be critical if personalised medicine is ever to become a reality.

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The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children

Abstract: Our data provide evidence that sirolimus seems to be effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing.

Cited by 64 publications

References 24 publications

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin

Genome‐wide association studies in Crohn's disease: Past, present and future

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