Showing papers by "Stephan R. Targan published in 2007"
TL;DR: It is demonstrated that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium, and these findings suggest thatAutophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
Abstract: We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
1,766 citations
TL;DR: Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalIZumab as induction therapy in patients with elevated C-reactive protein and active Crohn's disease.
587 citations
TL;DR: A panel of gastroenterologists expert in the area of inflammatory bowel disease (IBD) developed this consensus statement based on expert presentations of current scientific knowledge about IBD and through subsequent group discussion.
222 citations
TL;DR: Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.
Abstract: Crohn’s disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that is then triggered was widely considered to be a T-helper-1 mediated condition in Crohn’s disease and T-helper-2 mediated condition in ulcerative colitis. Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.
182 citations
TL;DR: It is demonstrated thatTL1A production in monocytes leads to enhancement of T cell responses, which suggests a role for TL1A in Th1 responses to pathogens, and in CD.
Abstract: The recently described TL1A/DR3 ligand/receptor pair mediates strong costimulation of Th1 cells. Activation of T and NK cells induces DR3 expression, permitting soluble recombinant TL1A to increase IFN-gamma production and proliferation of these cells. Gut T cells and macrophages express TL1A, especially in Crohn's disease (CD), and there is a strong association between CD and tl1a single nucleotide polymorphisms. Murine studies implicate TL1A in gut inflammation. To determine whether professional T cell-activating cells can express TL1A, fresh blood monocytes and monocyte-derived dendritic cells were stimulated with various activating ligands, including TLR agonists, IFN-gamma, and immune complexes. FcgammaR stimulation strongly induced TL1A mRNA in both cell types, which correlated with the detection of TL1A on the cell surface and in cell culture medium. TLR agonists capable of inducing IL-6 and TNF-alpha in monocytes and dendritic cells did not induce surface nor soluble TL1A. Furthermore, we demonstrate that TL1A production in monocytes leads to enhancement of T cell responses. The induction of TL1A on APCs via specific pathway stimulation suggests a role for TL1A in Th1 responses to pathogens, and in CD.
149 citations
TL;DR: The initial whole genome association study based on ileal CD in adults has been extended to the pediatric population and beyond small bowel CD, finding the protective IL‐23R R381Q variant was particularly associated with CD in non‐Jewish children.
Abstract: The currently accepted etiopathogenic hypothesis suggests that chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease (IBD) are due to an overly aggressive or pathologic immune response to resident luminal bacterial constituents. Predisposing factors are genetic dysregulation of mucosal immune responses and/or barrier function, with onset triggered by environmental stimuli. The increased level of concordance between identical twins, increased rates of IBD among the Ashkenazi Jewish population, and the familial risk of IBD provides strong evidence that genetic factors play an important role in the pathogenesis of IBD.1
Genetic advances have lead to the discovery that variants of CARD15 located at 16q12 and the 5q31 (IBD5) haplotype confer susceptibility to Crohn’s disease (CD). However, the risks associated with these 2 genes account for only a portion of the overall genetic risk. This has led to additional gene findings efforts, the most recent being the recent genome-wide association study that identified the association of the interleukin 23 receptor gene (IL-23R) with small bowel CD. In that study the rare glutamine allele of Arg381Gln (R381Q single nucleotide polymorphism, SNP) conferred protection against CD.2 Distortion of allele transmission was also observed for non-Jewish ulcerative colitis (UC)-affected offspring. This study was conducted in an adult IBD cohort and it remains unknown whether IL-23R is associated with IBD in children.
The IL-23R, consisting of an IL-12β1 and an IL-23R chain, is highly expressed on memory T cells.3 IL-23 is a novel cytokine formed via the binding of IL-12p40 to a p19 protein.4 After binding to the IL-23 receptor, IL-23 preferentially activates memory T cells. IL-23 does exhibit some similar biological activities to IL-12, however, IL-12 is more involved in the differentiation of naive T cells into TH1 lymphocytes and subsequent IFNγ production. IL-23, on the other hand, mediates proinflammatory activities in part by the production of IL-17 through activation of TH17 lymphocytes.5 Other research has shown that IL-23 increases IL-6 production that may account for the tissue injury characteristic of IBD.6 It has also been shown that IL-23, not IL-12, is an important promoter of chronic joint inflammation.5 Becker et al7 suggested that there is a predisposition of IL-23-induced chronic inflammation in the terminal ileum, which strengthens the evidence for the recent association between IL-23R in small bowel CD patients.2 The elevation of IL-17 levels in the colonic mucosa of both CD and UC patients, combined with the recent association of IL-23R with UC,2 suggests that IL-23 may also play an important role in UC.8
In this study the association of IL-23R in a pediatric IBD population was tested using the robust method of transmission disequilibrium test (TDT) analysis. We specifically tested R381Q SNP, since this was the most significant result in the genome-wide association study.
145 citations
TL;DR: Although preoperative treatment with infliximab alone does not significantly increase the incidence of postoperative complications, using both inflixiamb and cyclosporine A before colectomy in refractory ulcerative colitis is associated with high surgical morbidity.
Abstract: Purpose
Since infliximab has been approved for treatment of patients with refractory ulcerative colitis, surgeons will be increasingly faced with operating on patients who have failed therapy with this potent immunosuppressant. This study was designed to compare short-term complications in patients with ulcerative colitis who were treated with and without infliximab before colectomy.
140 citations
TL;DR: Visilizumab had an acceptable safety profile at the 10-microg/kg dose level and may be clinically beneficial in patients with severe intravenous corticosteroid-refractory ulcerative colitis.
134 citations
TL;DR: Patients with Crohn's disease and unaffected relatives carrying variants of the NOD2 gene have increased adaptive immune responses to microbial antigens.
126 citations
TL;DR: The magnitude of anti‐CBir1 reactivity, when added to the quantitative response toward the other 3 CD‐associated antigens, enhances the discrimination of FS, IP, UC‐like CD, and SB involvement, but not SB surgery.
Abstract: Background: Antibody reactivity to microbial antigens correlates with distinct Crohn's disease (CD) phenotypes such as fistulizing or fibrostenosing disease. We examined the association between anti-CBir1 and clinical phenotypes and NOD2 variants in a large cohort of adult CD patients.
Methods: Sera and genomic DNA were collected from 731 patients with CD and tested for immune responses to I2, CBir1, oligomannan, and outer membrane porin C (OmpC) and the 3 most common CD-associated NOD2 variants.
Results: Anti-CBir1 reactivity was significantly associated with fibrostenosis (FS), internal penetrating (IP) disease phenotypes, small bowel (SB) involvement, and SB surgery but negatively associated with ulcerative colitis (UC)-like CD. Multivariate logistic regression analysis showed that anti-CBir1 was independently associated with FS and UC-like CD irrespective of the antibody reactivity to I2, oligomannan, or OmpC, but not with SB involvement or SB surgery. The magnitude of anti-CBir1 reactivity, when added to the quantitative response toward the other 3 CD-associated antigens, enhances the discrimination of FS, IP, UC-like CD, and SB involvement, but not SB surgery. Finally, although the frequency of anti-CBir1 was similar in patients with none versus at least 1 NOD2 variant, the quantitative response to CBir1 flagellin was significantly higher in patients with CD carrying at least 1 NOD2 variant versus those carrying no variants (median anti-CBir1 titer 33.39 versus 28.36, respectively; P = 0.01).
Conclusions: Anti-CBir1 serum reactivity in CD patients is independently associated with FS and complicated SB CD. Quantitative, but not qualitative, response to CBir1 is also significantly associated with the CD-associated NOD2 variants.
(Inflamm Bowel Dis 2007)
116 citations
TL;DR: Clinical factors associated with AP included use of steroids before colectomy and smoking, and factors directly related to CP were extraintestinal manifestations, elevated platelet count, and length of follow-up after IPAA.
TL;DR: The data indicate that C CR9+ T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.
Abstract: CCL25/CCR9 chemokine ligand/receptor pair has been reported to play an important role in small bowel (SB) immunity and inflammation. We have previously reported an aberrant SB expression of CCL25 in Crohn’s disease (CD) and an increased frequency of CCR9 + T cells in the peripheral blood of patients with SB inflammatory diseases such as CD and celiac disease. In this study, we have characterized the phenotype and effector function of CCR9 + T cells in mucosal lymphoid tissues in CD. We show that CCR9 + T cells isolated from mesenteric lymph nodes (MLN) draining CD SB express a more activated phenotype compared with MLN draining normal SB. Stimulation of CCR9 + T cells isolated from CD SB lamina propria produced more IFN-γ and IL-17 in response to anti-CD3 or IL-12/IL-18 stimulation compared with those isolated from normal SB. The addition of TL1A to the cytokine combination markedly augmented the secretion of IFN-γ, but not IL-17, by CD lamina propria CCR9 + T cells. CCL25 incubation of CD SB lamina propria lymphocytes and MLN lymphocytes increased their adhesion to VCAM-1/Fc in vitro. Finally, the TCRVβ analysis of CCR9 + T cells revealed a diverse TCRVβ repertoire among MLN CCR9 + T cells in patients with SB CD. Our data indicate that CCR9 + T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.
TL;DR: A protective haplotype, consisting of the minor alleles for all 5 markers, to have a higher frequency in the non‐Jewish controls than in CD and UC, concluding that TNFSF15 is indeed an IBD susceptibility gene, and the disease susceptibility is ethnic‐specific.
Abstract: Background:Inflammatory bowel disease (IBD) is a clinically and, likely, genetically heterogeneous group of disorders. A recent report suggests that genetic variations in the TNFSF15 gene contribute to the susceptibility of IBD in both Japanese and Caucasian populations. The aim was to confi
TL;DR: Patients with a diagnosis of UC with initial non-bloody diarrhea or weight loss have an increased likelihood of subsequent change in diagnosis to CD and might thus warrant further diagnostic work-up.
TL;DR: These findings associate CD56+ T cells with the intestinal immune compartment and suggest a putative effector function in human mucosal immunity.
Abstract: T cells are key mediators of intestinal immunity, and specific T cell subsets can have differing immunoregulatory roles in animal models of mucosal inflammation. In this study, we describe human CD56 + T cells as a morphologically distinct population expressing a mature, nonproliferative phenotype that is frequent in the gut. Enhanced potential for IFN-γ and TNF synthesis suggested a proinflammatory function, and we directly demonstrate effector function mediated by direct T-T interaction with responder cells in vitro. CD56 + T cells from peripheral blood responded to the gut-related CD2 signal, and were necessary for effective CD2-mediated proliferation of peripheral blood CD56 − T cells. Our findings associate CD56 + T cells with the intestinal immune compartment and suggest a putative effector function in human mucosal immunity.
TL;DR: There is emerging evidence that discriminating pathogenic abnormalities are present in certain clusters of patients, defined by selected immune responses, and this review will describe the most recent advances and discuss promising pathways for therapeutic discovery.
Abstract: PURPOSE OF REVIEW Progress in inflammatory bowel disease, aided by use of animal models, and focused on pathways leading to inflammation and the relationship between the innate and adaptive immune systems, is identifying target pathogenic mechanisms for therapeutic intervention. This review will describe the most recent advances and discuss promising pathways for therapeutic discovery. RECENT FINDINGS Identification and testing of immune and genetic markers to distinguish subgroups of patients with inflammatory bowel disease have surged over the last decade. What was limited to a few serum antibodies is now complemented with a number of genetic associations. Recent years have seen renewed interest, with additional evidence on the relationship between intestinal commensal bacteria and the inflammatory process in Inflammatory bowel disease. SUMMARY There is emerging evidence that discriminating pathogenic abnormalities are present in certain clusters of patients, defined by selected immune responses. These traits have been used to identify correlates between relevant mouse models and immunophenotypic clusters of patients. Such approaches will not only help us to more easily define groups of patients for study, but will also enhance our understanding of the interface between various pathways and disease expression, and ultimately, identify the primal therapeutic targets in the appropriate subgroups of patients.
Patent•
05 Apr 2007TL;DR: In this article, a method for determining whether a human having Crohn's disease is likely to respond to a therapy targeting a TNFSF member or a cytokine by measuring the level of certain mRNAs in response to a stimulus is disclosed.
Abstract: A method is disclosed for determining whether a human having Crohn's disease is likely to respond to a therapy targeting a TNFSF member or a cytokine by measuring the level of certain mRNAs in response to a stimulus. A method of evaluating the effectiveness of a Crohn's disease therapy in a human is also disclosed. Furthermore, a method of screening compounds for use in the treatment of Crohn's disease is disclosed. A method of monitoring the disease state over time in Crohn's disease patients is also disclosed.
Patent•
05 Apr 2007TL;DR: In this article, a method for determining whether a human having Crohn's disease is likely to respond to a therapy targeting a TNFSF member or a cytokine by measuring the level of certain mRNAs in response to a stimulus is disclosed.
Abstract: A method is disclosed for determining whether a human having Crohn's disease is likely to respond to a therapy targeting a TNFSF member or a cytokine by measuring the level of certain mRNAs in response to a stimulus. A method of evaluating the effectiveness of a Crohn's disease therapy in a human is also disclosed. Furthermore, a method of screening compounds for use in the treatment of Crohn's disease is disclosed. A method of monitoring the disease state over time in Crohn's disease patients is also disclosed.