Ulcerative Colitis: Targan SR

Shih DQ, Targan SR, McGovern D. · Cedars-Sinai Inflammatory Bowel Disease Center, 8700 Beverly Boulevard, Suite D4059, Los Angeles, CA 90048, USA. · Curr Gastroenterol Rep. · Pubmed #19006613 No free full text.

Abstract: The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders caused by dysregulated immune responses in genetically predisposed individuals. Although the precise etiology of IBD remains unclear, accumulating data, including genome-wide association studies, have advanced our understanding of its immunopathogenesis. This review highlights the role in gut homeostasis and IBD pathogenesis of autophagy, the interleukin (IL)-23/IL-17 axis, and a novel member of the tumor necrosis factor family, TL1A. It focuses on advances in our understanding of IBD from the past year, including advances in genetics and immunobiology.

Shih DQ, Targan SR. · Cedars-Sinai Inflammatory Bowel Disease Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA. · World J Gastroenterol. · Pubmed #18200661 links to  free full text

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.

Isaacs KL, Lewis JD, Sandborn WJ, Sands BE, Targan SR. · University of North Carolina, Chapel Hill, North Carolina, USA. · Inflamm Bowel Dis. · Pubmed #16254481 No free full text.

Abstract: Inflammatory bowel diseases (IBD) encompass Crohn's disease and ulcerative colitis, which are diseases characterized by chronic intestinal inflammation. IBD is believed to result from predisposing genetic and environmental factors (specific antigens and pathogen-associated molecular patterns) acting on the immunoregulatory system and causing inflammation of the gastrointestinal mucosa. IBD may be the result of an imbalance of effector (proinflammatory) and regulatory T-cell responses. Three scenarios indicative of the outcome of this balance exist in animal models: balanced effector and regulatory T cells resulting in a normal controlled inflammation; overactive effector T cells resulting in inflammation and disease; and an absence of regulatory T cells resulting in uncontrolled inflammation and severe, aggressive disease. The number of products under study for the treatment of IBD has increased from 3 products and 1 target in 1993 to more than 30 products and more than 10 targets in 2005. The number of products under development and continued investigations into the pathogenesis of IBD emphasize the need to expand clinical research efforts in IBD.

Targan SR, Karp LC. · Division of Gastroenterology, Inflammatory Bowel Disease Center, Immunobiology Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Immunol Rev. · Pubmed #16048556 No free full text.

Abstract: Evidence accumulated over the last decade demonstrates that what we call 'ulcerative colitis' is actually a heterogeneous group of diseases resulting from different pathogenic mechanisms with a common symptomatic expression. Subgroups of patients with ulcerative colitis can be stratified by presence or absence of serum autoantibodies, which are thought not to be pathogenic but to mark for a distinct disease phenotype. In recent years, animal-based experimental systems have emerged that reflect human ulcerative colitis and have potential to accelerate our understanding of its pathogenesis. Genetic and immunological data from human studies in combination with results from animal model systems are the foundation of a hypothesis, which includes a role for microbial antigen exposure in the initiation, perpetuation, and amplification of the disease. In ulcerative colitis, it appears as though the T-cell response to the antigens is not T-helper (Th) 1 dominant as in the case of Crohn's disease but rather is either Th2 [interleukin (IL)-4, IL-13] or is mediated by specialized cells such as natural killer (NK) T cells (IL-13). Lamina propria T cells from ulcerative colitis patients produce significantly greater amounts of IL-13. Ulcerative colitis is associated with an atypical Th2 response mediated by a distinct subset of NK T cells that produce IL-13 and are cytotoxic for epithelial cells. The way in which this response affects the ultimate cascade of inflammatory events has yet to be determined.

Sandborn WJ, Targan SR. · Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA. · Gastroenterology. · Pubmed #12016425 No free full text.

Abstract: Advancing knowledge regarding the biology of chronic inflammation has led to the development of specific biologic therapies that mechanistically target individual inflammatory pathways. Many biologic therapies are being evaluated for the treatment of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis. Biologic compounds proven to be effective for Crohn's disease include monoclonal antibodies to tumor necrosis factor (infliximab and CDP571) and to the leukocyte adhesion molecule alpha4 integrin (natalizumab). Other biologic compounds for which there is insufficient evidence to judge efficacy for inflammatory bowel disease include: p55 tumor necrosis factor binding protein (onercept); interferon alpha; interferon beta-1a; anti-interferon gamma antibody; anti-interleukin 12 antibody; p65 anti-sense oligonucleotide (blocks NF-kappaB); granulocyte colony stimulating factor, and granulocyte macrophage colony stimulating factor; anti-interleukin 2 receptor antibody; epidermal growth factor; keratinocyte growth factor 2 (repifermin); human growth hormone; anti-CD4 antibody; and anti-alpha4beta7 antibody. Biologic therapies that have been proven ineffective for inflammatory bowel disease include: interleukin 10; interleukin 11; anti-sense intercellular adhesion molecule-1; and the tumor necrosis factor receptor fusion protein etanercept. Based on the early successes of infliximab, CDP571 and natalizumab, it seems certain that biologic therapy will play an important role in the future treatment of inflammatory bowel disease.

Papadakis KA, Targan SR. · *Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, D-4062, Los Angeles, CA 90048, USA. · Curr Gastroenterol Rep. · Pubmed #10980990 No free full text.

Abstract: Serologic testing in inflammatory bowel disease provides a unique tool to classify these diseases into more homogeneous groups. Serum markers can also be used to identify common antigenic triggers and specific defects in mucosal immune regulation and cytokine imbalance in different parts of the gastrointestinal tract. ANCA (antineutrophil cytoplasmic antibodies) and ASCA (anti-Saccharomyces cerevisiae antibodies), the most extensively studied serologic markers, have been used to classify ulcerative colitis and Crohn's disease into such groups with certain phenotypic characteristics and responses to treatment. Similar studies have been initiated in indeterminate colitis, and these results will help in the future to define the immunopathogenesis, prognosis, and response to certain treatments in patients with this type of disease.

Papadakis KA, Targan SR. · Division of Gastroenterology, Cedars-Sinai Medical Center, University of California, Los Angeles 90048, USA. · Annu Rev Med. · Pubmed #10774465 No free full text.

Abstract: Recent advances in the drug treatment of inflammatory bowel disease (IBD) have paralleled our understanding of the pathophysiology of ulcerative colitis and Crohn's disease. Several proinflammatory and immune-regulatory cytokines are upregulated in the mucosa of patients with IBD, and differences and similarities in the cytokine profiles of ulcerative colitis and Crohn's disease have been elucidated. Several clinical trials involving a chimeric anti-TNF-alpha (tumor necrosis factor-alpha) antibody have shown marked clinical benefit in the majority of patients with Crohn's disease, verifying the importance of TNF-alpha in the pathogenesis of Crohn's disease. In preliminary studies, treatment with recombinant human interleukin-10 has been beneficial in Crohn's disease but not in ulcerative colitis. Future treatment of IBD may include combination or sequential cytokine and anticytokine administration in defined groups of patients based on their mucosal cytokine profiles.

Baumgart DC, Lowder JN, Targan SR, Sandborn WJ, Frankel MB. · Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt University of Berlin, Berlin, Germany. · Am J Gastroenterol. · Pubmed #19240707 No free full text.

Abstract: OBJECTIVES: Monoclonal antibodies to CD3 and CD4 T-cell receptors are evolving for Crohn's disease (CD) and ulcerative colitis. Their administration is often associated with a cytokine release syndrome (CRS).METHODS:We evaluated data from two prospective clinical trials (NCT00267709 and NCT00267722) of visilizumab (HuM291), a novel humanized anti-CD3 antibody, in 34 patients with CD who received 10 microg/kg intravenously on 2 consecutive days. Serum hepatic tests including bilirubin, alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), visilizumab concentrations, and a panel of 16 cytokines were measured pre- and postadministration of visilizumab. RESULTS: Patients experienced CRS symptoms at a median of 45 min postinfusion. The cytokine profile was characterized by interferon-inducible protein-10 (IP-10), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, monocyte chemotactic protein 1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-2 (IL-2), and interleukin 1 receptor antagonist (IL-1Ra), which were elevated between 6 (IL-1Ra) and 870 (IP-10) times their baseline concentrations. TNF-alpha and IL-2 peaked at the first day 1 h post infusion, whereas all others peaked at 6 h post infusion. Eighty-six percent of patients experienced an elevation above the upper limit of normal in hepatic enzymes (GGT 73%, AST 73%, ALT 64%, and AP 42% of patients), but not bilirubin, within 6 h postinfusion. CONCLUSIONS: Transient elevation of hepatic enzymes occurred frequently in patients with CD treated with visilizumab and was associated with CRS. CD patients could be predisposed due to an aberrant expression of adhesion molecules in the liver that promotes CRS upon engagement of the T-cell receptor and may relate to extraintestinal disease manifestations such as primary sclerosing cholangitis.

Sands BE, Tremaine WJ, Sandborn WJ, Rutgeerts PJ, Hanauer SB, Mayer L, Targan SR, Podolsky DK. · Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston 02114, USA. · Inflamm Bowel Dis. · Pubmed #11383595 No free full text.

Abstract: We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.

Murrell ZA, Melmed GY, Ippoliti A, Vasiliauskas EA, Dubinsky M, Targan SR, Fleshner PR. · Department of Surgery, Division of Colon and Rectal Surgery, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Dis Colon Rectum. · Pubmed #19502850 No free full text.

Abstract: PURPOSE: The long-term outcome of ileal pouch-anal anastomosis in patients with indeterminate colitis is controversial. The aim of this study was to prospectively evaluate the long-term outcome of ileal pouch-anal anastomosis in a closely monitored cohort of patients with ulcerative colitis or indeterminate colitis. METHODS: Prospectively generated clinical profiles on consecutive patients with ulcerative colitis or indeterminate colitis undergoing ileal pouch-anal anastomosis with close postoperative follow-up by one surgeon were reviewed. All patients were classified before surgery as either ulcerative colitis or inflammatory bowel disease-unclassified, and after surgery as either ulcerative colitis or indeterminate colitis. Long-term outcomes included acute pouchitis (antibiotic responsive), chronic pouchitis (antibiotic dependent or refractory), or de novo Crohn's disease (small inflammation above the pouch inlet or pouch fistula). RESULTS: The study cohort of 334 patients were classified before surgery as ulcerative colitis in 237 (71 percent) and inflammatory bowel disease-unclassified in 97 (29 percent). After surgery, patients were classified as ulcerative colitis in 236 (71 percent) and indeterminate colitis in 98 (29 percent). After a median follow-up after stoma closure of 26 months, 53 patients (16 percent) developed acute pouchitis, 37 patients (11 percent) developed chronic pouchitis, and 40 patients (12 percent) developed de novo Crohn's disease. There was no significant difference in the incidence of acute pouchitis, chronic pouchitis, or de novo Crohn's disease between the ulcerative colitis, inflammatory bowel disease-unclassified, and indeterminate colitis patient groups. CONCLUSION: The incidence of acute pouchitis, chronic pouchitis, and de novo Crohn's disease after ileal pouch-anal anastomosis do not differ significantly between patients with ulcerative colitis, inflammatory bowel disease-unclassified, or indeterminate colitis. Patients with inflammatory bowel disease-unclassified and indeterminate colitis can undergo ileal pouch-anal anastomosis and expect a long-term outcome equivalent to patients with ulcerative colitis.

Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. · No affiliation provided · Nat Genet. · Pubmed #19471306 No free full text.

This publication has no abstract.

Michelsen KS, Thomas LS, Taylor KD, Yu QT, Mei L, Landers CJ, Derkowski C, McGovern DP, Rotter JI, Targan SR. · Inflammatory Bowel Disease Center & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. · PLoS One. · Pubmed #19262684 links to  free full text

Abstract: BACKGROUND: The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-gamma production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts. METHODOLOGY AND PRINCIPAL FINDINGS: Here we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P< or =0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcgammaR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype. CONCLUSIONS AND SIGNIFICANCE: These findings suggest that TL1A gene variation exacerbates induction of TL1A in response to FcgammaR stimulation in Jewish CD patients and this may lead to chronic intestinal inflammation via overwhelming T cell responses. Thus, TL1A may provide an important target for therapeutic intervention in this subgroup of IBD patients.

Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. · Mount Sinai Hospital Inflammatory Bowel Disease Group, University of Toronto, 600 University Avenue, Toronto, ON M5G1X5, Canada. · Nat Genet. · Pubmed #19122664 links to  free full text

Abstract: Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Saruta M, Targan SR, Mei L, Ippoliti AF, Taylor KD, Rotter JI. · Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, California 90048, USA. · Inflamm Bowel Dis. · Pubmed #18942751 No free full text.

Abstract: BACKGROUND: TNF-alpha and IL-1 have been associated with mucosal inflammation in both Crohn's disease (CD) and ulcerative colitis (UC). Innate immune defects have been associated with CD, specifically CARD15/NOD2. Recently, Toll-like receptor 8 (TLR8) signaling has been shown to enhance generation of both cytokines. Interestingly, TLR8 is located on the X chromosome and inflammatory bowel disease (IBD) has been associated with abnormalities of the X chromosome. The aim was to test whether TLR8 haplotypes are associated with IBD. METHODS: Subjects (735 CD, 343 UC, 245 controls) were genotyped. Single nucleotide polymorphisms (SNPs) were chosen to tag common Caucasian haplotypes. RESULTS: Both "risk (H4)" and "protective (H1)" TLR8 haplotypes were observed associated with CD in females. Eighteen percent of CD females had H4 compared with 9% of controls (P = 0.02). Fifty-nine percent of CD females had H1 compared with 72% of controls (P = 0.01). H1 was also negatively associated with UC in females (59% of UC, 72% of controls P = 0.03). Diplotype analysis of CD, UC, and all IBD in females revealed that 2 protective haplotypes (H1/H1) had a markedly diminished odds ratio, 0.4-0.5. The presence of a risk haplotype (H4 / not H1) had a significantly increased odds ratio, 2.0-2.2. Thus, the risk for IBD was 4-5 times higher in females with 1 risk haplotype than with the protective/protective diplotype. CONCLUSIONS: TLR8 is an X-linked IBD susceptibility gene with both common predisposing and protecting haplotypes. These associations further emphasize the importance of genetic variation in innate immunity as determinants, not only of CD, but of UC as well.

Shen C, Landers CJ, Derkowski C, Elson CO, Targan SR. · Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Inflamm Bowel Dis. · Pubmed #18825772 No free full text.

Abstract: BACKGROUND: CBir1 is a dominant antigen with a role in innate and adaptive immunity in mouse models of colitis and antibodies to CBir1 are associated with severe human Crohn's disease (CD). Our aim was to determine whether CBir1 stimulates innate and antigen-specific T-cell responses in CD. We demonstrate that CBir1 enhanced IL-6 and IL-1beta production by peripheral blood (PB) monocytes. METHODS: Real time polymerase chain reaction (PCR) was used for measurement of IL6 and IL1 expression. [(3)H] thymidine was used to measure T cell proliferation and Elispot assay was used to measure IFNgamma production. RESULTS: IL-6 was significantly increased in monocytes from CD compared to controls and ulcerative colitis (UC). Anti-CBir1(+) patients and IL-6 was inversely correlated. A significant increase in CBir1-specific peripheral T-cell proliferation was more evident in cells from CD than controls and UC. CBir1 induced increased numbers of IFN-gamma(+) cells in lamina propria mononuclear cells (LPMC) from CD compared to UC and controls. CONCLUSIONS: CBir1 induces enhanced peripheral innate and peripheral and mucosal antigen-specific T-cell responses in CD. Consistent with results from the mouse, CBir1 immune activation could play a role in CD.

McGovern DP, Taylor KD, Landers C, Derkowski C, Dutridge D, Dubinsky M, Ippoliti A, Vasiliauskas E, Mei L, Mengesha E, King L, Pressman S, Targan SR, Rotter JI. · Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Inflamm Bowel Dis. · Pubmed #18720471 No free full text.

Abstract: BACKGROUND: Despite recent advances the majority of inflammatory bowel disease (IBD) susceptibility 'genes' remain undiscovered. Recent data suggest that autoimmune conditions may 'share' susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens. METHODS: We genotyped 113 MAGI2 single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls. RESULTS: The most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti-Saccharomyces cerevisiae antibodies (ASCA)-positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti-CBir1-positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti-outer membrane porin C (OmpC)-positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, P = 0.0003 and anti-IgG ASCA, P = 0.0002). CONCLUSIONS: These findings support the significance of the epithelial barrier in IBD pathogenesis.

Mitsuhashi M, Targan SR. · Hitachi Chemical Research Center, Inc., Irvine, California, USA. · Inflamm Bowel Dis. · Pubmed #18340639 links to  free full text

Abstract: BACKGROUND: Human leukocyte IgG Fc receptors (FcgammaR) and T-cell receptors (TCR) are primary molecules involved in inflammatory and immune pathways. METHODS: These 2 receptors were stimulated in whole blood for 2-4 hours with immune complex and specific agonistic antibody, respectively, and various mRNAs were quantified by a method we developed previously. RESULTS: FcgammaR stimulation induced tumor necrosis factor superfamily 2 (TNFSF2), TNFSF8, TNFSF15, interleukin 1B (IL1B), IL8, CCL chemokine 2 (CCL2), CCL3, CCL4, CCL11, CCL20, CXCL chemokine 1 (CXCL1), CXCL2, and CXCL3 mRNA, whereas TCR stimulation induced different subsets of mRNA such as TNFSF1, TNFSF2, TNFSF5, TNFSF6, TNFSF9, TNFSF14, IL6, CCL2, CCL8, CCL20, and CXCL10. Interestingly, respondents and nonrespondents were identified for each mRNA. When we applied this method to inflammatory bowel disease, the respondent populations of TCR-induced TNFSF2 (= TNFalpha), TNFSF5, TNFSF14, CCL2, CCL8, and CCL20 mRNA were significantly higher in Crohn's disease (CD) patients than in healthy controls or those with ulcerative colitis (UC). No difference was found for FcgammaR-mediated responses. The respondent population of TCR-induced TNFSF2 showed significantly (P = 0.05) higher incidence of multiple surgeries than did nonrespondents. CONCLUSIONS: These data demonstrate an underlining hyperfunction of TCR in peripheral-blood leukocytes in CD patients. The ex vivo simulation demonstrates an underlining hyperfunction of TCR in peripheral-blood leukocytes in CD patients and may form the basis of a relatively noninvasive test for distinguishing these IBDs.

Melmed GY, Fleshner PR, Bardakcioglu O, Ippoliti A, Vasiliauskas EA, Papadakis KA, Dubinsky M, Landers C, Rotter JI, Targan SR. · Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Dis Colon Rectum. · Pubmed #18085333 links to  free full text

Abstract: PURPOSE: Approximately 5 to 10 percent of patients undergoing ileal pouch-anal anastomosis with a diagnosis of ulcerative colitis are subsequently diagnosed with Crohn's disease. Preoperative predictors for Crohn's disease post-ileal pouch-anal anastomosis have not been prospectively defined. METHODS: A total of 238 consecutive patients with ulcerative colitis or indeterminate colitis undergoing ileal pouch-anal anastomosis were prospectively enrolled into a longitudinal database. Clinical factors were assessed perioperatively. Serum drawn preoperatively was assayed for anti-Saccharomyces cerevisiae, antiouter membrane porin-C, anti-CBir1, and perinuclear antineutrophil cytoplasmic antibody using enzyme-linked immunosorbent assay. Crohn's disease was defined by small bowel inflammation proximal to the ileal pouch or a perianal fistula identified at least three months after ileostomy closure. Predictors were assessed in a multivariate Cox proportional hazards model to predict the rate of Crohn's disease after ileostomy closure. RESULTS: Sixteen patients (7 percent) were diagnosed with Crohn's disease; median time to Crohn's disease was 19 (range, 1-41) months. Significant factors for postoperative Crohn's disease after ileal pouch-anal anastomosis included family history of Crohn's disease (hazard ratio, 8.4; 95 percent confidence interval, 2.96-24.1; P < 0.0001) and anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity (hazard ratio, 3.14; 95 percent confidence interval, 1.1-9.81; P = 0.04). Crohn's disease developed in only 8 of 198 patients (4 percent) without these predictors vs. 8 of 40 patients (20 percent) in those with at least one of these factors (P = 0.002). The cumulative risk of Crohn's disease among patients with two risk factors (67 percent) was higher than in patients with either risk factor (18 percent) or neither risk factor (4 percent, P < 0.001). CONCLUSIONS: Patients with ulcerative colitis and indeterminate colitis with a family history of Crohn's disease or preoperative anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity are more likely to be diagnosed with Crohn's disease after ileal pouch-anal anastomosis.

Vandewalle-El Khoury P, Colombel JF, Joossens S, Standaert-Vitse A, Collot M, Halfvarson J, Ayadi A, Landers CJ, Vermeire S, Rutgeerts P, Targan SR, Chamaillard M, Mallet JM, Sendid B, Poulain D. · Inserm, U799, Lille, France. · Am J Gastroenterol. · Pubmed #18047546 No free full text.

Abstract: OBJECTIVES: Anti-S. cerevisiae mannan antibodies (ASCA) are human antibodies associated with Crohn's disease (CD) reacting with Saccharomyces cerevisiae (S. cerevisiae) mannan polymer. As mannan is a complex and variable repertoire of oligomannoses acting as epitopes, we chemically synthesized (Sigma) two major oligomannose epitopes, Man alpha-1,3 Man alpha-1,2 Man (SigmaMan3) and Man alpha-1,3 Man alpha-1,2 Man alpha-1,2 Man (SigmaMan4), and then explored how antisynthetic mannoside antibodies (ASigmaMA) compare with ASCA as markers of CD. METHODS: The study involved different cohorts of CD and ulcerative colitis (UC) patients and healthy controls who had been studied previously in several medical centers in Europe, the United States, and North Africa to determine the clinical value of ASCA in terms of differential diagnosis, evolution of indeterminate colitis (IC), and serotype-phenotype correlations. The comparison of ASigmaMA and ASCA included a total of 1,365 subjects: 772 CD, 261 UC, 43 IC, and 289 controls. RESULTS: The specificity of ASigmaMA was similar to that of ASCA (89% vs 93%), although the sensitivity was lower (38% vs 55%). Unexpectedly, 24% of the CD patients who were negative for ASCA and/or other CD-associated serologic markers were positive for ASigmaMA. ASigmaMA were associated with colonic involvement in CD (odds ratio [OR] 1.609, 95% confidence interval [CI] 1.033-2.506, P = 0.03) and were 100% predictive of CD in patients with IC. CONCLUSIONS: ASigmaMA reveal the heterogeneity of the antioligomannose antibody response in CD patients and increase the sensitivity of CD diagnosis when combined with ASCA. The subset of ASCA-negative CD patients diagnosed by ASigmaMA had preferentially a colonic involvement, which confirms the high predictive value of ASigmaMA for determining IC evolution toward CD.

Schluender SJ, Ippoliti A, Dubinsky M, Vasiliauskas EA, Papadakis KA, Mei L, Targan SR, Fleshner PR. · Division of Colon and Rectal Surgery, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8737 Beverly Boulevard, Suite 101, Los Angeles, California 90048, USA. · Dis Colon Rectum. · Pubmed #17704969 No free full text.

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. METHODS: The charts of patients undergoing ileal pouch-anal anastomosis or subtotal colectomy for refractory ulcerative colitis during the five-year period ending October 2005 were reviewed. Postoperative medical and surgical complications were assessed. RESULTS: Seventeen patients had failed infliximab treatment and 134 patients were never treated with infliximab. Ileal pouch-anal anastomosis was performed in 112 patients (74 percent) and subtotal colectomy in 39 patients (36 percent). There were no deaths. Postoperative complications were observed in 43 patients (28 percent), with no significant difference observed between infliximab-treated (37 percent) and infliximab-untreated patients (27 percent). Of 61 patients (40 percent) treated with preoperative cyclosporine A, 5 patients also had been treated with infliximab. The infliximab and cyclosporine A-treated patient group had an 80 percent complication rate, significantly higher than the 29 percent complication rate noted in the cyclosporine A only-treated group (P = 0.04). CONCLUSIONS: 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.

Picornell Y, Mei L, Taylor K, Yang H, Targan SR, Rotter JI. · Medical Genetics Institute, Cedars-Sinai Medical Center Los Angeles, California, USA. · Inflamm Bowel Dis. · Pubmed #17663424 links to  free full text

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 confirm the association between TNFSF15 high- and low-risk haplotypes and IBD in a Caucasian population. METHODS: Five single-nucleotide polymorphisms (SNPs) that comprise the 2 common haplotypes were genotyped in 599 Caucasian patients with Crohn's disease (CD), 382 Caucasian patients with ulcerative colitis (UC), and 230 ethnically matched healthy controls, including both Jews and non-Jews. RESULTS: The previously reported 'risk' haplotype was not associated with CD or UC (88.2% in CD cases versus 88.3% in controls, P = 0.96; 88.1% in UC cases versus 88.3% in controls, P = 0.78). We did, however, observe an increased frequency of the "protective" haplotype in non-Jewish controls for both CD and UC (38.8% CD cases versus 50% controls, P = 0.01; 37.3% UC cases versus 50% controls, P = 0.01) with no such effect observed in the Jewish samples. There was an interactive effect between ethnicity and the protective haplotype in CD (P = 0.04). CONCLUSIONS: We observed 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. Of further interest, the haplotype frequency was in the opposite direction in our Jewish case-control panels (both CD and UC), leading us to conclude 1) that TNFSF15 is indeed an IBD susceptibility gene, and 2) the disease susceptibility is ethnic-specific.

Melmed GY, Elashoff R, Chen GC, Nastaskin I, Papadakis KA, Vasiliauskas EA, Liu W, Landers C, Ippoliti AF, Targan SR. · Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California Los Angeles, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #17478347 No free full text.

Abstract: BACKGROUND & AIMS: Some patients diagnosed with UC undergo a change in diagnosis to CD. Identification of predictors of a diagnostic change could potentially impact the management of patients with colonic inflammation. Our aim was to characterize clinical and serologic predictors of a change in diagnosis from UC to CD. METHODS: A nested, case-controlled study was performed to compare individuals with a change in diagnosis from UC to CD (cases) with age-matched UC and CD controls; primary analysis compared cases with UC controls. Subjects underwent chart review for clinical "red flags" identified by gastroenterologists with expertise in IBD. Serum collected at the time of database enrollment was tested for antibodies to oligomannan (anti-Saccharomyces cerevisiae), Pseudomonas fluorescens-related protein, Escherichia coli outer membrane porin C, CBir1 flagellin, and perinuclear antineutrophil cytoplasmic antibodies. RESULTS: Twenty-one cases, 52 UC controls, and 56 CD controls were assessed. Three red flags, but no serologic markers, differed between cases and UC controls. At initial colonoscopy, cases were more likely to have extensive colonic involvement than UC controls (P = .008). Multivariate regression identified non-bloody diarrhea at initial presentation (P = .01) and weight loss >10% at presentation (P = .007) as independent predictors of diagnostic change. Serologic markers did not add to the contribution of these 2 clinical factors in predicting a change in diagnosis from UC to CD. Diagnostic change was evident in 6 of 6 (100%) patients with both predictors, compared with 8 of 50 (16%) with neither of these factors (P < .0001). CONCLUSIONS: 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.

Dubinsky MC, Wang D, Picornell Y, Wrobel I, Katzir L, Quiros A, Dutridge D, Wahbeh G, Silber G, Bahar R, Mengesha E, Targan SR, Taylor KD, Rotter JI, Anonymous00160. · Department of Pediatrics, Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Inflamm Bowel Dis. · Pubmed #17309073 links to  free full text

Abstract: BACKGROUND: The IL-23 receptor (IL-23R) has been found to be associated with small bowel Crohn's disease (CD) in a whole genome association study. Specifically, the rare allele of the R381Q single nucleotide polymorphism (SNP) conferred protection against CD. It is unknown whether IL-23R is associated with IBD in children. The aim was to examine the association of IL-23R with susceptibility to IBD in pediatric patients. METHODS: DNA was collected from 609 subjects (151 CD and 52 ulcerative colitis [UC] trios). Trios were genotyped for the R381Q SNP of the IL-23R gene and SNP8, SNP12, SNP13, of the CARD15 gene using Taqman. The transmission disequilibrium test (TDT) was used for association to disease using GENEHUNTER 2.0. RESULTS: The rare allele of R381Q SNP was present in 2.7% of CD and 2.9% UC probands. The CARD15 frequency was 31.5% (CD) and 18% (UC). The IL-23R allele was negatively associated with inflammatory bowel disease (IBD): the R381Q SNP was undertransmitted in children with IBD (8 transmitted [T] versus 27 untransmitted [UT]; P = 0.001). This association was significant for all CD patients (6 T versus 19 UT; P = 0.009), especially for non-Jewish CD patients (2 T versus 17 UT; P = 0.0006). TDT showed a borderline association for UC (2 T versus 8 UT; P = 0.06). As expected, CARD15 was associated with CD in children by the TDT (58 T versus 22 UT P = 0.00006), but not with UC. CONCLUSIONS: The protective IL-23R R381Q variant was particularly associated with CD in non-Jewish children. Thus, the initial whole genome association study based on ileal CD in adults has been extended to the pediatric population and beyond small bowel CD.

Papadakis KA, Yang H, Ippoliti A, Mei L, Elson CO, Hershberg RM, Vasiliauskas EA, Fleshner PR, Abreu MT, Taylor K, Landers CJ, Rotter JI, Targan SR. · Cedars-Sinai Inflammatory Bowel Disease Center, Los Angeles, California, USA. · Inflamm Bowel Dis. · Pubmed #17260364 links to  free full text

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.

Elson CO, Cong Y, Qi F, Hershberg RM, Targan SR. · Division of Gastroenterology and Hepatology, The University of Alabama-Birmingham, 633 Zeigler Research Building, 703 S. 19th Street, Birmingham, AL 35294-0007, USA. · Ann N Y Acad Sci. · Pubmed #17057189 No free full text.

Abstract: The microbiota plays a crucial role in experimental models of inflammatory bowel disease, but the exact mechanisms of its effects are unknown. These studies took two molecular approaches to this question. The first used amplification of the 16s ribosomal DNA to define microbial diversity in the colon. Although there were differences in colitic and non-colitic mice, we could not determine whether this was primary or secondary to the disease. The second approach used serologic expression cloning to identify the microbial proteins stimulating the pathogenic immune response. Previously unknown microbial flagellins were the dominant cluster of antigens identified. About half of the sera from patients with Crohn's disease have IgG antibodies to these flagellins.