Autoimmune Inflammtory Bowel Diseases: Crohn’s Disease & Ulcerative Colitis: Potential Roles for Modulation of Interleukins 17 and 23 Signaling for Therapeutics

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Autoimmune Inflammtory Bowel Diseases: Crohn’s Disease & Ulcerative Colitis: Potential Roles for Modulation of Interleukins 17 and 23 Signaling for Therapeutics

January 23, 2016 by 2012pharmaceutical

Autoimmune Inflammtory Bowel Diseases: Crohn’s Disease & Ulcerative Colitis – Potential Roles for Modulation of Interleukins 17 and 23 Signaling for Therapeutics

Curators: Larry H Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

Edited: 1/25/2016

Sarepta Therapeutics, Corvallis, Oregon, has been assigned a patent (9,238,042) – “antisense modulation of interleukins 17 and 23 signaling.”

01/21/2016 | 07:08am US/Eastern
By Targeted News Service

ALEXANDRIA, Va., Jan. 21 — Sarepta Therapeutics, Corvallis, Oregon, has been assigned a patent (9,238,042) developed by four co-inventors for “antisense modulation of interleukins 17 and 23 signaling.” The co-inventors are Frederick J. Schnell, Corvallis, Oregon, Patrick L. Iversen, Corvallis, Oregon, Dan V. Mourich, Albany, Oregon, and Gunnar J. Hanson, Bothell, Washington.

The patent application was filed on May 13, 2011 (13/107,528). The full-text of the patent can be found at

http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=92,38,042.PN.&OS=PN/92,38,042&RS=PN/92,38,042

Written by Deviprasad Jena; edited by Jaya Anand.

http://www.4-traders.com/SAREPTA-THERAPEUTICS-INC-11204214/news/Sarepta-Therapeutics-Assigned-Patent-21723050/

Sarepta Therapeutics Corvallis

United States Patent	9,238,042
Schnell , et al.	January 19, 2016

Antisense modulation of interleukins 17 and 23 signaling

Abstract Provided are antisense oligonucleotides and other agents that target and modulate IL-17 and/or IL-23 signaling activity in a cell, compositions that comprise the same, and methods of use thereof. Also provided are animal models for identifying agents that modulate 17 and/or IL-23 signaling activity.

http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=92,38,042.PN.&OS=PN/92,38,042&RS=PN/92,38,042

On PubMed

Immunity. 2015 Oct 20;43(4):739-50. doi: 10.1016/j.immuni.2015.08.019. Epub 2015 Sep 29.

Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation.

Maxwell JR¹, Zhang Y¹, Brown WA¹, Smith CL¹, Byrne FR², Fiorino M², Stevens E³, Bigler J⁴, Davis JA⁵, Rottman JB⁶, Budelsky AL¹, Symons A¹, Towne JE⁷.

Author information

Abstract

Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn’s disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn’s disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn’s disease when IL-17A or IL-17RA is inhibited.

Comment in

Gut-Busters: IL-17 Ain’t Afraid of No IL-23. [Immunity. 2015]

PMID:: 26431947; [PubMed – in process]; http://www.ncbi.nlm.nih.gov/pubmed/26431947

Immunity. 2015 Oct 20;43(4):620-2. doi: 10.1016/j.immuni.2015.10.001.

Gut-Busters: IL-17 Ain’t Afraid of No IL-23.

Whibley N¹, Gaffen SL².

Author information

Abstract

Interleukin-23 (IL-23) is considered a critical regulator of IL-17 in lymphocytes. Whereas antibodies targeting IL-23 ameliorate colitis, IL-17 neutralization exacerbates disease. In this issue, Cua and colleagues and Maxwell and colleagues show that IL-17 maintains intestinal barrier integrity, helping explain this dichotomy (Lee et al., 2015; Maxwell et al., 2015).

Comment on

Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. [Immunity. 2015]
Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. [Immunity. 2015]

PMID:: 26488809; [PubMed – in process]; http://www.ncbi.nlm.nih.gov/pubmed/26488809

Gut. 2014 Dec;63(12):1902-12. doi: 10.1136/gutjnl-2013-305632. Epub 2014 Feb 17.

Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn’s disease.

Honzawa Y¹, Nakase H¹, Shiokawa M¹, Yoshino T¹, Imaeda H², Matsuura M¹, Kodama Y¹, Ikeuchi H³,Andoh A², Sakai Y⁴, Nagata K⁵, Chiba T¹.

Author information

Abstract

OBJECTIVE:

Intestinal fibrosis is a clinically important issue in Crohn’s disease (CD). Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone involved in fibrotic diseases. The molecular mechanisms of HSP47 induction in intestinal fibrosis related to CD, however, remain unclear. Here we investigated the role of interleukin (IL)-17A-induced HSP47 expression in intestinal fibrosis in CD.

DESIGN:

Expressions of HSP47 and IL-17A in the intestinal tissues of patients with IBD were determined. HSP47 and collagen I expressions were assessed in intestinal subepithelial myofibroblasts (ISEMFs) isolated from patients with IBD and CCD-18Co cells treated with IL-17A. We examined the role of HSP47 in IL-17A-induced collagen I expression by administration of short hairpin RNA (shRNA) to HSP47 and investigated signalling pathways of IL-17A-induced HSP47 expression using specific inhibitors in CCD-18Co cells.

RESULTS:

Gene expressions of HSP47 and IL-17A were significantly elevated in the intestinal tissues of patients with active CD. Immunohistochemistry revealed HSP47 was expressed in α-smooth muscle actin (α-SMA)-positive cells and the number of HSP47-positive cells was significantly increased in the intestinal tissues of patients with active CD. IL-17A enhanced HSP47 and collagen I expressions in ISEMFs and CCD-18Co cells. Knockdown of HSP47 in these cells resulted in the inhibition of IL-17A-induced collagen I expression, and analysis of IL-17A signalling pathways revealed the involvement of c-Jun N-terminal kinase in IL-17A-induced HSP47 expression.

CONCLUSIONS:

IL-17A-induced HSP47 expression is involved in collagen I expression in ISEMFs, which might contribute to intestinal fibrosis in CD.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

KEYWORDS:

Crohn’s disease (CD); Fibrosis; Heat shock protein (HSP); Myofibroblasts

PMID:

24534724

[PubMed – indexed for MEDLINE]

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/24534724

Dr. Larry H Bernstein voice on

Involvement of interleukin-17A-induced expression of heat shock protein 47

The tie is very interesting. The IL17A association with fibrosis in Crohn’s may be unrelated to UC. Ulcerative colitis only affects the superficial mucosa. This is where the GI people have not been specific enough. It is also the case that UC can extend to the ligament of Treitz, that separates small and large bowel. I can’t grasp it all and have not had to think about this for perhaps a decade.

The points of interest are:

1) the circulation of the small bowel, ascending and transverse colon are superior mesenteric artery. (I don’t recall if it is to midtransverse colon).

2) the circulation to the descending colon is the inferior mesenteric artery.

3) this might have some bearing on the issue of oxidative stress.

The microbiome resides in the large intestine, which seems to work in concert with the microbiome with respect to E. coli and enterobacter. In this case you only get superficial mucosal erosion, which is by no means not serious, but not associated with deep invasion of the muscularis.

The deeply invasive Crohn’s regional enteritis may extend as far as the midtransverse colon, but not as a rule. Isn’t it interesting that the more invasive disease is not at the “home” of the microbiome.

There has been very interesting research reported in the Sunday NY Times about the “autopsy” and determining the time of death. There is a postmortem transition in the microbiome referred to as the “necrobiome”.

Inflamm Bowel Dis. 2008 Sep;14(9):1197-204. doi: 10.1002/ibd.20482.

Transcriptomic analysis of intestinal fibrosis-associated gene expression in response to medical therapy in Crohn’s disease.

Burke JP¹, Ferrante M, Dejaegher K, Watson RW, Docherty NG, De Hertogh G, Vermeire S, Rutgeerts P,D’Hoore A, Penninckx F, Geboes K, Van Assche G, O’Connell PR.

Author information

Abstract

BACKGROUND:

Glucocorticoids and monoclonal antibodies to tumor necrosis factor reduce inflammation in Crohn’s disease (CD). Rapid luminal healing, however, may promote intestinal stricture formation. The aim of this study was to examine fibrosis-associated gene expression in the intestine of patients with CD and correlate expression levels with prior medical therapies.

METHODS:

In all, 37 patients with stricturing CD and 18 non-CD controls underwent a transmural biopsy at the time of elective intestinal resection. Quantitative real-time polymerase chain reaction (PCR) was conducted to determine differential mRNA expression of TGF-beta(1), Smad-7, CTGF, collagen-1alpha, fibronectin, BMP-7, and MIF. Intestinal fibroblasts were treated in vitro with dexamethasone.

RESULTS:

Relative to control, strictured CD intestinal tissue expressed increased TGF-beta(1), CTGF, collagen-1alpha, and BMP-7 (all P < 0.05). TGF-beta(1) gene expression positively correlated with the expression of its downstream targets (all P < 0.001). Preoperative infliximab exposure was not associated with increased expression in any of the target genes nor did the number of infliximab infusions correlate with gene expression. The number of cycles of corticosteroid treatment preoperatively was positively associated with CTGF (r = 0.486, P = 0.016) and MIF (r = 0.524, P = 0.009) expression. Intestinal fibroblasts treated in vitro with dexamethasone upregulated CTGF expression (P = 0.023).

CONCLUSIONS:

Exposure to infliximab does not appear to induce a profibrotic transcriptional response in the CD intestine. Previous corticosteroid treatment is associated with increased expression of CTGF and MIF. Treating intestinal fibroblasts in vitro with steroids upregulates CTGF expression.

PMID: 18452219

[PubMed – indexed for MEDLINE]

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/18452219

J Interferon Cytokine Res. 2013 Jul;33(7):355-68. doi: 10.1089/jir.2012.0063. Epub 2013 Mar 8.

IL-23/IL-17A axis correlates with the nitric oxide pathway in inflammatory bowel disease: immunomodulatory effect of retinoic acid.

Rafa H¹, Saoula H, Belkhelfa M, Medjeber O, Soufli I, Toumi R, de Launoit Y, Moralès O, Nakmouche M,Delhem N, Touil-Boukoffa C.

Author information

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn’s disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.

PMID: 23472658

[PubMed – indexed for MEDLINE]

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/23472658

Inflamm Bowel Dis. 2014 Jul;20(7):1250-8. doi: 10.1097/MIB.0000000000000043.

Mechanisms that mediate the development of fibrosis in patients with Crohn’s disease.

Li C¹, Kuemmerle JF.

Author information

Abstract

Crohn’s disease is complicated by the development of fibrosis and stricture in approximately 30% to 50% of patients over time. The pathogenesis of fibrostenotic disease is multifactorial involving the activation of mesenchymal cells by cytokines, growth factors, and other mediators released by immune cells, epithelial cells, and mesenchymal cells. Transforming growth factor β, a key activator of mesenchymal cells, is central to the process of fibrosis and regulates numerous genes involved in the disordered wound healing including collagens, and other extracellular matrix proteins, connective tissue growth factor, and insulin-like growth factors. The activated mesenchymal compartment is expanded by recruitment of new mesenchymal cells through epithelial to mesenchymal transition, endothelial to mesenchymal transition, and invasion of circulating fibrocytes. Cellular hyperplasia and increased extracellular matrix production, particularly collagens, from fibroblasts, myofibroblasts, and smooth muscle cells add to the disturbed architecture and scarring on the intestine. Extracellular matrix homeostasis is further disrupted by alterations in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinase in the gut. Among the 163 susceptibility genes identified that contribute to susceptibility in inflammatory bowel disease mutations in NOD2/CARD15, innate immune system components and autophagy jointly contribute to the activation of mesenchymal cells and pathogenesis of fibrosis in this polygenic disorder. Numerous growth factors cytokines and other mediators also contribute to development of fibrosis in the susceptible patient. This review focuses on the molecular mechanisms that regulate mesenchymal cell function, particularly smooth muscle cells, the largest compartment of mesenchyme in the intestine, that lead to fibrosis in Crohn’s disease.

PMID:: 24831560; [PubMed – indexed for MEDLINE]
PMCID:: PMC4057349

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/24831560

REFERENCES

On Crohn’s

Cytokines in Crohn’s colitis.

Sher ME, D’Angelo AJ, Stein TA, Bailey B, Burns G, Wise L.

Am J Surg. 1995 Jan;169(1):133-6.

PMID: 7817982 [PubMed – indexed for MEDLINE]

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Autoimmune Inflammtory Bowel Diseases: Crohn’s Disease & Ulcerative Colitis: Potential Roles for Modulation of Interleukins 17 and 23 Signaling for Therapeutics

Autoimmune Inflammtory Bowel Diseases: Crohn’s Disease & Ulcerative Colitis – Potential Roles for Modulation of Interleukins 17 and 23 Signaling for Therapeutics

Sarepta Therapeutics, Corvallis, Oregon, has been assigned a patent (9,238,042) – “antisense modulation of interleukins 17 and 23 signaling.”

On PubMed

Author information

Abstract

Comment in

Author information

Abstract

Comment on

Dr. Larry H Bernstein voice on

Involvement of interleukin-17A-induced expression of heat shock protein 47

Author information

Abstract

BACKGROUND:

METHODS:

RESULTS:

CONCLUSIONS:

Author information

Abstract

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