Brian Ko

Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis.

TL1A is a member of the TNF superfamily and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, a subset of Crohns disease (CD) patients with the risk TL1A haplotype is associated with elevated TL1A expression and a more severe disease course. To investigate the in vivo role of elevated TL1A expression, we generated two transgenic (Tg) murine models with constitutive Tl1a expression in either lymphoid or myeloid cells. Compared to wildtype (WT) mice, constitutive expression of Tl1a in either lymphoid or myeloid cells showed mild patchy inflammation in the small intestine, which was more prominent in the ileum. In addition, mice with constitutive Tl1a expression exhibited enhanced intestinal and colonic fibrosis compared to WT littermates. The percentage of T cells expressing the gut homing chemokine receptors CCR9 and CCR10 was higher in the Tl1a Tg mice compared to WT littermates. Sustained expression of Tl1A in T cells also lead to increased Foxp3+ Treg cells. T cells or antigen presenting cells (APC) with constitutive expression of Tl1a were found to have a more activated phenotype and mucosal mononuclear cells exhibit enhanced Th1 cytokine activity. These results indicated an important role of TL1A in mucosal T cells and APC function and showed that up-regulation of TL1A expression can promote mucosal inflammation and gut fibrosis.

HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T-cell proliferation and TH1/TH17 responses.

Background:Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double-blind, placebo-controlled trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate ulcerative colitis (UC). We aimed to determine if HMPL-004 could prevent the development of T-cell-dependent murine colitis and to define its in vivo mechanism(s) of action. Methods:CD4+CD45RBhigh T cells were transferred into Rag1−/− mice and gavaged daily with HMPL-004 or methyl cellulose (MC). Severity of colitis was evaluated by weight loss, histology, and cytokine expression. Results:Mice treated with MC developed colitis within 4–7 weeks, as evaluated by weight loss, and severe intestinal inflammation. HMPL-004-treated mice did not lose weight and displayed only very mild intestinal inflammation. Tumor necrosis factor alpha (TNF-&agr;), interleukin (IL)-1&bgr;, interferon-gamma (IFN-&ggr;), and IL-22 expression were significantly decreased in HMPL-004-treated mice. We observed higher percentages of naïve CD4+ T cells in the lamina propria of HMPL-004-treated mice. At early timepoints HMPL-004-treated mice have significantly reduced splenic cell counts, reduced CD4+, and IL-17+, and IFN-&ggr;+ T cells. Furthermore, HMPL-004 inhibited the proliferation of CD4+ T cells and differentiation into TH1/TH17 cells in vitro. Conclusions:HMPL-004 inhibits the development of chronic colitis by affecting early T-cell proliferation, differentiation, and TH1/TH17 responses in a T-cell-driven model of colitis, presenting a unique mechanism of action. Our data suggest that HMPL-004 could be an attractive herbal therapeutic for inflammatory bowel disease.

Functional signaling of membrane‐bound TL1A induces IFN‐γ expression

TL1A, a TNF member implicated in autoimmune diseases, is a transmembrane protein that is processed to release soluble TL1A (TL1A‐S). TL1A‐S induces a Th1 response, although the functional significance of membrane‐bound TL1A (TL1A‐M) remains unknown. We generated TL1A‐M expression in HEK‐293 cells capable of binding DR3‐Fc. Co‐incubating IL‐12/IL‐18‐primed CD4+ T cells with HEK‐293 cells expressing TL1A‐M induced 3‐fold increase in IFN‐γ that was blocked by anti‐TL1A Ab. These results demonstrate that TL1A‐M can bind death domain receptor 3 (DR3) through cell–cell contact to induce downstream IFN‐γ secretion enhancement. Anti‐TL1A antibodies designed to treat immune diseases should be verified to block both endogenous TL1A forms.

Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis

Background and aim Bile acid (BA) synthesis in the liver is regulated by Fibroblast Growth Factor 19 (FGF19) secreted from the ileum as an enterohepatic feedback mechanism. Although FGF19 mRNA is absent in normal liver, FGF19 gene expression was reported to increase in response to both extrahepatic and intrahepatic cholestasis. The impact of upregulated FGF19 expression on BA synthesis is unclear and the overall role of circulating FGF19 and BA synthesis under cholestatic conditions needs to be further investigated. Methods BA synthesis was directly quantified by measuring serum concentrations of 7alpha-hydroxycholest-4-en-3-one (C4), along with serum FGF19 and other parameters, in 44 patients with primary biliary cirrhosis (PBC) and 10 healthy subjects. Results Serum C4 were substantially lower, while those of FGF19 were higher, in cirrhotic PBC patients, as compared to those of either healthy or non-cirrhotic PBC patients. Analyses of the relationships between circulating FGF19, BA synthesis and cholestasis revealed that circulating FGF19 was strongly correlated with BA synthesis (r = -0.735, p<0.0001) and the severity of cholestasis (r = 0.590, p<0.001). Moreover, BA synthesis was found to be strongly correlated with the degree of cholestasis (r = 0.522, p = 0.0005). Conclusion These findings demonstrate that the regulation of BA synthesis in response to cholestasis is primarily controlled by circulating FGF19 and that under cholestatic conditions, the FGF19-BA synthesis feedback mechanism remains intact. Administering FGF19, or suitable mimetic, as a pharmacological intervention to increase circulating levels of FGF19 and suppress BA synthesis by inhibiting CYP7A1 gene expression is likely to provide therapeutic benefits for many PBC patients.

S1174 UC Patients With High Level Antibody Responses to CD-Associated Microbial Antigens Exhibit Aberrant IFNG DNA Methylation Patterns

AIM: Colonic polyps are causally related to the nearly 150,000 yearly incident cases of colon cancer in the USA. The study aim was to identify and quantitate variables that affect polyp size in a large sample of patients undergoing CS for indications of routine screening or family history of colorectal cancer. METHODS: 93,110 adult patients from 67 GI practices in 25 states undergoing CS who had colorectal polyps on exam were identified in the Clinical Outcomes Research Initiative (CORI) database. Polyp size of the largest polyp was the outcome variable; patient age, race, gender, type of practice, anatomic location, and indication for procedure were independent variables. Ten-year age bands were used to stratify patient age; the size of the largest polyp in each patient was stratified into four ordinal groups (05 mm, 5.1-9, 9.1-15, >15 mm). Ordinal logistic regression was used to obtain multivariateadjusted estimates of polyp size in relation to patient age. RESULTS: For patients 80 years. After multivariate adjustment, odds of having a larger polyp increased with each increasing age group, compared to those under 50 years (see Table). The odds ratio for polyp size in the oldest age group versus youngest age group was 1.61 (95% CI = 1.46-1.77, p = <0.0001). Other factors with multivariate-adjusted significant odds ratios were gender (males vs females 1.18, P = <0.0001), race (blacks versus whites 1.33, P = <0.0001), practice type (community vs academic 1.26, P = <0.0001), and polyp location (distal vs proximal colon 0.89, P = <0.0001). CONCLUSION: Size of the largest polyp detected at CS increases significantly with age, and among variables included in a multivariate model, age has the strongest association with polyp size.