Kori Wallace

Immunopathology of inflammatory bowel disease

Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. The host microbiome, as well as viruses and fungi, play important roles in the development of IBD either by causing inflammation directly or indirectly through an altered immune system. New technologies have allowed researchers to be able to quantify the various components of the microbiome, which will allow for future developments in the etiology of IBD. Various components of the mucosal immune system are implicated in the pathogenesis of IBD and include intestinal epithelial cells, innate lymphoid cells, cells of the innate (macrophages/monocytes, neutrophils, and dendritic cells) and adaptive (T-cells and B-cells) immune system, and their secreted mediators (cytokines and chemokines). Either a mucosal susceptibility or defect in sampling of gut luminal antigen, possibly through the process of autophagy, leads to activation of innate immune response that may be mediated by enhanced toll-like receptor activity. The antigen presenting cells then mediate the differentiation of naïve T-cells into effector T helper (Th) cells, including Th1, Th2, and Th17, which alter gut homeostasis and lead to IBD. In this review, the effects of these components in the immunopathogenesis of IBD will be discussed.

Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis

Intestinal fibrostenosis is among the hallmarks of severe Crohn’s disease. Patients with certain TNFSF15 (gene name for TL1A) variants over-express TL1A and have a higher risk of developing strictures in the small intestine. In addition, sustained Tl1a expression in mice leads to small and large intestinal fibrostenosis under colitogenic conditions. The aim of this study was to determine whether established murine colonic fibrosis could be reversed with Tl1a antibody (Ab). Treatment with neutralizing Tl1a Ab reversed colonic fibrosis back to the original pre-inflamed levels, potentially as a result of lowered expression of connective tissue growth factor, Il31Ra, transforming growth factor β1 and insulin-like growth factor-1. In addition, blocking Tl1a function by either neutralizing Tl1a Ab or deletion of death domain receptor 3 (Dr3) reduced the number of fibroblasts and myofibroblasts, the primary cell types that mediate tissue fibrosis. Primary intestinal myofibroblasts expressed Dr3 and functionally responded to direct Tl1a signaling by increasing collagen and Il31Ra expression. These data demonstrated a direct role for TL1A–DR3 signaling in tissue fibrosis and that modulation of TL1A–DR3 signaling could inhibit gut fibrosis.

783 TL1A Modulates the Differential Effect of IL-17 Blockade on Mucosal Inflammation

Background: IL-17 has been thought to be pathogenic in IBD. However, a recent clinical trial using IL-17 blockade unexpectedly worsened IBD (Hueber, et al. Gut. 2012). A proportion of trial patients who responded to IL-17 blockade were found to carry a risk TL1A IBD polymorphism that predicted elevated expression of TL1A. The mechanism of IL-17 and its interaction with TL1A on mucosal inflammation has not been found. Aim: To determine the mechanism of TL1A mediated differential effects of IL-17 on mucosal inflammation Methods: Naive (CD4+CD45RBhi) T-cells were isolated from WT, Tl1a-Tg, Il-17a-/-, and Tl1a-Tg with deficiency in Il-17a (Tl1a-Tg/Il-17a-/-) mice and adoptively transferred into Rag-/mice. Naive (CD4+CD25loCD44loCD62hi) T-cells were differentiated in vitro into T helper (Th) effector cells. Intestinal inflammation was evaluated by disease activity index (DAI) and histological analyses. Flow cytometry was used to determine CD4+ T-cell infiltration, activation, and cytokine expression in the LPMC from the colon. Results: Consistent with the human IL-17 trial, we found that mice that received Il-17a-/Naive cells had worsened colitis (increased DAI scores and cecal inflammation) as compared to WT. Comparable results were seen with Tl1a-Tg Naive cells. Similar to the human IL-17 trial, Il-17a deficiency under Tl1a driven conditions (Tl1a-Tg/Il-17a-/-) ameliorated colitis (reduced DAI and cecal inflammation). Mucosal CD4+ T-cell infiltration and activation (CD69 and CD44) were increased in both Il-17a-/and Tl1a-Tg, but reduced with Tl1a-Tg/Il-17a-/-. Analysis of Th effector pathways demonstrated a shift towards Th-1 (increased Ifn-γ) and Th-9 (increased Il-9), and reduced regulatory cytokine Il-10 production with both Il-17a-/and Tl1a-Tg. In contrast, Il-17 deficiency under Tl1a driven conditions (Tl1a-Tg/Il-17a-/-) had a reduction in Th1 (reduced Ifn-γ) and Th9 (reduced Il-9) responses, and increased regulatory responses (increased Il-10). To assess whether intrinsic cellular differences exist in Naive T-cells between WT, Il-17a-/-, Tl1a-Tg, and Tl1a-Tg/Il-17a-/-, in vitro differentiation assays were performed. Consistently, in vitro differentiated Naive Il-17a-/and Tl1a-Tg T-cells expressed increased Ifn-γ and Il-9, whereas Tl1a-Tg/Il17a-/T-cells expressed lower Il-9 but higher Il-10 levels. Conclusion: IL-17 blockade induces mucosal inflammation by enhancing Th1 and Th9 effector pathways and reducing regulatory response. However under TL1A driven conditions, inhibiting IL-17 may be beneficial by reducing Th1 and Th9 effector responses and enhancing regulatory responses. This may be one mechanism of why the subset of IBD patients with TL1A polymorphisms improved with IL-17 blockade, while most trial patients did not. This highlights the importance of understanding pathway-pathway interactions in designing clinical trials. Table 1: Inflammatory Markers

Selective IL-23 inhibition by risankizumab modulates the molecular profile in the colon and ileum of patients with active Crohn's disease: Results from a randomised phase II biopsy substudy.

Abstract Background and Aims We aimed to investigate the underlying mechanism of action of risankizumab, a monoclonal antibody targeting the IL-23 p19 subunit, previously reported to induce clinical and endoscopic remission in a randomised phase II study in patients with active Crohn’s disease. Methods Ileum and colon biopsies obtained at screening and Week 12 from a subgroup of patients [n = 106] in the risankizumab phase II study were analysed by transcriptome-wide RNA-Seq profiling. Univariate associations were assessed using linear modelling. Results By Week 12, risankizumab significantly decreased [p < 0.005] the expression of 1880 and 765 genes in the colon [false-discovery rate = 0.02] and ileum [false-discovery rate = 0.05], respectively. These genes were associated with the IL-23/IL-17 axis, Th1 pathway, innate immunity, and tissue turnover. Colonic transcriptomic profiles following risankizumab treatment reflected the transcriptomic changes observed in patients achieving endoscopic response and remission at Week 12 and were significantly different from placebo [p < 0.005]. The colonic transcriptomic profile, significantly modulated by risankizumab at Week 12, was indicative of suppression of pathways associated with epithelial biology. Furthermore, pathways associated with Crohn’s disease modulated by risankizumab treatment included second messenger-mediated signalling, immune response, lymphocyte and leucocyte activation, lymphocyte differentiation and cell–cell adhesion. Conclusions Endoscopic remission and response observed with risankizumab in patients with active Crohn’s disease was associated with significant transcriptomic changes in the colon, compared with placebo. Differentiated expression of genes associated with the IL-23/IL-17 axis was observed in the colon and ileum 12 weeks after risankizumab treatment.

Erratum: Sustained TL1A (TNFSF15) expression on both lymphoid and myeloid cells leads to mild spontaneous intestinal inflammation and fibrosis (DOI: 10.1556/EuJMI.3.2013.1.2).

After the publication of this article (EurJ Microbiol Immunol (Bp) 2013;3: , 13 Mar), we discovered that the version of Figure 3b included in the article is incorrect due to it being done for a separate project. Please see the correct Figure 3b file here. This change does not affect the summary data for Figure 3c, statistical analysis, or figure legend. Fig. 3b. Sustained Tl1a expression led to an increased expression of activation and gut homing marker on Tl1a-Tg T cells.

Efficacy and Safety of Dose Escalation to Adalimumab 80 mg Every Other Week in Japanese Patients with Crohn’s Disease Who Lost Response to Maintenance Therapy

Background: Dose escalation is often recommended for loss of response in anti-TNFα-treated patients with Crohn’s disease (CD). This 52-week phase 3, multicenter study investigated the efficacy and safety of escalation to adalimumab 80 mg every other week (EOW) in Japanese patients with CD who lost response to maintenance adalimumab 40 mg EOW. Methods: Twenty-eight patients aged ≥15 years with moderately to severely active CD who had previously attained and subsequently lost clinical response to maintenance ada limumab received open-label adalimumab 80 mg EOW during weeks 0–50. Loss of response was defined as CD activity index (CDAI) ≥200, increases in CDAI ≥50 from minimum observed value, and C-reactive protein (CRP) ≥1 mg/dL at screening. The primary endpoint was the proportion of patients achieving a CDAI decrease ≥50 (CR-50) from baseline at week 8. Results: At weeks 8 and 52, 75.0 and 57.1% of patients achieved CR-50 and 25.0 and 35.7% achieved clinical remission (CDAI < 150), respectively; median CRP changes from baseline were −0.39 and −0.77 mg/dL, respectively. Most treatment-emergent adverse events were mild to moderate. Conclusions: Adalimumab dose escalation to 80 mg EOW improved CD activity in patients who had lost response to maintenance adalimumab, with no new safety signals. (ClinicalTrials.gov Identifier: NCT01958827.)

Sa1131 PYRAMID Registry: An Observational Study of Adalimumab in Crohn's Disease: Results at Year 6

Background: This study evaluated the long-term safety of adalimumab (ADA), as used in routine clinical practice, for up to 6 years in patients with moderately to severely active Crohns disease (CD) enrolled in the global observational registry PYRAMID. Methods: All patients entering the multi-centre, non-interventional registry PYRAMID were to be followed for up to 6 years. Adverse events (AEs) were collected from the first dose to up to 70 days after the last dose of ADA or through the cutoff of 1 December 2013. AE rates are reported as per 100 patient-years (PY). Results: A total of 5061 patients (57.1% female, mean age 37.8 years, median duration of CD 8.2 years) have enrolled in PYRAMID, totaling 13924.3 PY of ADA exposure, excluding prior exposure in CD ADA clinical trials. As of 01 Dec 2013, 2885 patients (57%) were still participating and 297 patients (5.9%) had at least 6 years of ADA exposure. A total of 2600 patients (51%) received biologic therapy prior to enrollment (98.3% infliximab, 5.6% certolizumab, 1.4% natalizumab, 0.5% other). During the study, concomitant corticosteroids (CS), immunosuppressants (IMM), and IMM + CS were used by 29.4%, 35.6%, and 11.6% of patients, respectively. A total of 682 patients (4.9/100 PY) experienced serious infections, of which 265 patients (5.1/100 PY) were on combination therapy with IMM and 417 patients (4.8/100 PY) were on ADA monotherapy. A total of 104 patients (0.7/100 PY) experienced any malignancy, of which 50% had received combination therapy with IMM. Thirty-eight treatment-emergent deaths (0.3/100 PY) were reported, of which 7 were considered possibly related to ADA. Overall, ADA-exposed patients did not have an increased mortality versus the general population. The Table shows an overview of exposure-adjusted registry treatment-emergent AEs for years 3, 5, and 6. Conclusion: After up to 6 years of observation, long-term ADA exposure continued to be welltolerated in patients with moderately to severely active CD. No new safety signals were identified. AE rates remained stable over time. Table. Cumulative incidence of treatment-emergent adverse events (AEs) excluding prior exposure in other CD ADA trials