Ulcerative Colitis: Cominelli F

Bickston SJ, Cominelli F. · No affiliation provided · Clin Gastroenterol Hepatol. · Pubmed #15017510 No free full text.

This publication has no abstract.

Bamias G, Cominelli F. · First Department of Propaedeutic Medicine, Laiko General Hospital, Athens, Greece, and Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, Virginia 22908, USA. · Curr Opin Gastroenterol. · Pubmed #17545770 No free full text.

Abstract: PURPOSE OF REVIEW: According to the current paradigm, ulcerative colitis and Crohn's disease occur in genetically predisposed individuals because of dysregulated immune responses against intraluminal bacterial antigens. Data have recently accumulated supporting alternative hypotheses for the pathogenesis of inflammatory bowel disease. Here, we present novel immunogenetic pathways and discuss their impact on traditional understanding of inflammatory bowel disease. RECENT FINDINGS: In the gastrointestinal tract the innate immune system contains intraluminal bacteria locally, avoiding invasion of the deeper layers and preventing induction of long-standing proinflammatory responses. Failure of this protective function of the innate immune system appears to be the primary defect in inflammatory bowel disease, as a result of impairment of NOD2 signaling or other unidentified deficiencies. The adaptive immune response that ensues was thought to be strictly differentiated between T-helper-1 mediated in Crohn's disease and T-helper-2 mediated in ulcerative colitis. This concept is rapidly changing, however, in light of recent evidence suggesting that tissue injury in inflammatory bowel disease is mediated by novel effector pathways, the most prominent of which is the interleukin-23/Th17 axis. SUMMARY: Elucidation of the pathways that underlie chronic intestinal inflammation will facilitate the development of new treatments with increased specificity and probably with decreased toxicity.

Pizarro TT, Cominelli F. · Division of Gastroenterology & Hepatology and the Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, Virginia 22908, USA. · Annu Rev Med. · Pubmed #17217333 No free full text.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC), the two idiopathic inflammatory bowel diseases (IBDs), affect almost two million individuals in North America and several million worldwide. Cytokines are important in the pathogenesis of CD, and their manipulation has successfully reduced disease severity and maintained remission. Following the discovery of novel cytokines and the role they may play in gut mucosal immunity, as well as the emergence of new concepts and changing paradigms in CD pathogenesis, the roles of several cytokines have been elucidated and tested in both preclinical animal models and clinical trials of patients with IBD. Complementary to this, proof of concept for new cytokine targets is rapidly developing, with the possibility of future cytokine-based therapies that may offer greater specificity and decreased toxicity for the treatment of CD. This review discusses novel concepts in CD pathogenesis and the roles of cytokines in the initiation and perpetuation of disease. In addition, we review applications of cytokine-based therapies in human clinical trials and preclinical animal studies. Finally, we discuss novel cytokine targets not yet investigated in vivo and describe their potential contribution to CD pathogenesis.

Arseneau KO, Cominelli F. · Digestive Health Center, Case Western Reserve University, Cleveland, OH, United States. · Dig Liver Dis. · Pubmed #19540820 No free full text.

This publication has no abstract.

Arseneau KO, Sultan S, Provenzale DT, Onken J, Bickston SJ, Foley E, Connors AF, Cominelli F. · Division of Gastroenterology & Hepatology, University of Virginia Health System, Charlottesville, Virginia, USA. · Clin Gastroenterol Hepatol. · Pubmed #16829206 No free full text.

Abstract: BACKGROUND & AIMS: Patients with steroid-refractory ulcerative colitis face a difficult treatment decision between colectomy and therapy with infliximab or cyclosporine. The aim of this study was to understand how individual patient preferences for the various treatment outcomes influence the optimal treatment decision for a given patient. METHODS: A Markov model was used to simulate treatment with total colectomy with an ileo pouch-anal anastomosis (TC/IPAA), cyclosporine (CSA), infliximab (INFLX), and infliximab followed by cyclosporine for treatment failures (INFLX-->CSA). Utility weights for treatment outcomes were elicited from 48 patients using both time trade-off and visual rating scale methods. Preference sets were applied to the model to identify the therapy that maximized quality-adjusted life years (QALYs) for each patient. Sensitivity analyses were performed to assess model robustness. RESULTS: Optimal treatment was highly variable among patients (INFLX-->CSA = 42%, 20/48; TC/IPAA = 37%, 18/48; CSA = 21%, 10/48; INFLX = 0%, 0/48). However, when average preference weights from our sample were applied to the model, medical treatments were superior to TC (CSA = .26 QALYs gained vs TC/IPAA; INFLX-->CSA = .25 QALYs gained vs TC/IPAA). CONCLUSIONS: Patient preferences have a clear impact on the optimal treatment for steroid-refractory ulcerative colitis. Although averaged preferences support the use of medical interventions, a third of individual patients may benefit most from proceeding directly to colectomy. Failure to fully assess individual preferences may result in suboptimal treatment for these patients.

Bamias G, Martin C, Marini M, Hoang S, Mishina M, Ross WG, Sachedina MA, Friel CM, Mize J, Bickston SJ, Pizarro TT, Wei P, Cominelli F. · Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. · J Immunol. · Pubmed #14568967 links to  free full text

Abstract: TL1A is a novel TNF-like factor that acts as a costimulator of IFN-gamma secretion through binding to the death domain-containing receptor, DR3. The aim of this study was to test the hypothesis that TL1A may play an important role in inflammatory bowel disease (IBD) by functioning as a Th1-polarizing cytokine. The expression, cellular localization, and functional activity of TL1A and DR3 were studied in intestinal tissue specimens as well as isolated lamina propria mononuclear cells from IBD patients and controls. TL1A mRNA and protein expression was up-regulated in IBD, particularly in involved areas of Crohn's disease (CD; p < 0.03 vs control). TL1A production was localized to the intestinal lamina propria in macrophages and CD4(+) and CD8(+) lymphocytes from CD patients as well as in plasma cells from ulcerative colitis patients. The amount of TL1A protein and the number of TL1A-positive cells correlated with the severity of inflammation, most significantly in CD. Increased numbers of immunoreactive DR3-positive T lymphocytes were detected in the intestinal lamina propria from IBD patients. Addition of recombinant human TL1A to cultures of PHA-stimulated lamina propria mononuclear from CD patients significantly augmented IFN-gamma production by 4-fold, whereas a minimal effect was observed in control patients. Our study provides evidence for the first time that the novel cytokine TL1A may play an important role in a Th1-mediated disease such as CD.

Tountas NA, Casini-Raggi V, Yang H, Di Giovine FS, Vecchi M, Kam L, Melani L, Pizarro TT, Rotter JI, Cominelli F. · Division of Gastroenterology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA. · Gastroenterology. · Pubmed #10500062 No free full text.

Abstract: BACKGROUND & AIMS: The role of the interleukin (IL)-1 receptor antagonist (IL-1ra) in predisposing an individual to inflammatory bowel disease (IBD) is controversial. This study aimed to determine the association between intron 2 IL-1ra polymorphism and IBD by performing a multiethnic case-control study and to assess its functional significance. METHODS: A total of 236 patients with ulcerative colitis (UC), 196 patients with Crohn's disease (CD), and 338 ethnically matched control patients treated at LAC-USC and Cedars-Sinai Medical Centers and the University of Milan Medical Center were genotyped for a variable length polymorphism in intron 2 of the IL-1ra gene (IL-1RN). Total IL-1ra protein production rates in peripheral blood mononuclear cells (PBMCs) were correlated with carriage of allele 2 of the IL-1RN gene (IL-1RN*2). RESULTS: In the LAC-USC group, UC patients (n = 60) had an increased frequency of at least 1 copy of IL-1RN*2 compared with controls (n = 129) (70% vs. 33%; P < 0.01; odds ratio [OR], 4.7). The frequency of IL-1RN*2 carriage in the Cedars-Sinai group was 59% in UC, 45% in CD, and 42% in controls (P < 0.01; OR, 2.0). A significant difference was observed only in the Jewish subgroup (P = 0.003; OR, 5.0). The association was not detected in UC or CD patients treated at the University of Milan. The ORs of 4.7 and 5.0 appear to be the highest reported in any UC population for any genetic markers. Further, carriage of IL-1RN*2 was associated with decreased production of total IL-1ra protein in cultured PBMCs from both UC patients and controls. CONCLUSIONS: These results provide further evidence that IL-1ra is important in the predisposition to UC, there may be genetic or pathogenetic heterogeneity between different ethnic groups, and UC and CD are genetically distinct diseases.

Pizarro TT, Michie MH, Bentz M, Woraratanadharm J, Smith MF, Foley E, Moskaluk CA, Bickston SJ, Cominelli F. · Department of Medicine, Digestive Health Center, University of Virginia Health Sciences Center, Charlottesville 22908, USA. · J Immunol. · Pubmed #10352304 links to  free full text

Abstract: IL-18, a novel immunoregulatory cytokine with potent IFN-gamma-inducing activities, may play an important role in Th1-mediated chronic inflammatory disorders. The aim of the present study was to characterize the expression and localization of IL-18 in colonic specimens and isolated mucosal cell populations from patients with Crohn's disease (CD), a prototypic Th1-mediated disorder. Using a semiquantitative RT-PCR protocol, IL-18 mRNA transcripts were found to be increased in freshly isolated intestinal epithelial cells (IEC) and lamina propria mononuclear cells (LPMC) from CD compared with ulcerative colitis (UC) and noninflamed control (cont) patients, and were more abundant in IEC compared with LPMC. Immunohistochemical analysis of surgically resected colonic tissues localized IL-18 to both LPMC (specifically, macrophages and dendritic cells) as well as IEC. Staining was more intense in CD compared with UC and cont, and in involved (inv) vs noninvolved (n inv) areas. Western blot analysis revealed that an 18. 3-kDa band, consistent with both recombinant and mature human IL-18 protein, was found predominantly in CD vs UC intestinal mucosal biopsies; a second band of 24 kDa, consistent with the inactive IL-18 precursor, was detected in n inv areas from both CD and UC biopsies and was the sole form found in noninflamed cont. To our knowledge, this report is the first describing increased expression of IL-18 in a human Th1-mediated chronic inflammatory disease. In addition, our studies further support the concept that IEC and dendritic cells may possess important immunoregulatory functions in both normal, as well as pathological, mucosal immunity.