Gerald W. Dryden

Gut immunology and the differential response to feeding and starvation

Animal and human research has established the beneficial effects of enteral nutrition on the gut. Both the innate and acquired immune systems are bolstered by enteral alimentation. Emerging clinical concepts tie these beneficial effects to a significant influence on the host immune response to stressors during critical illness. In this article, we examine how enteral nutrition impacts gastrointestinal immunity and demonstrate how these changes may affect the bodys systemic immune response to nongastrointestinal challenges. This modulatory effect occurs because of changes in the pattern of cytokine secretion and alterations in lymphocyte and neutrophil recruitment. Imbalances in these regulatory mechanisms may be the engine driving hyperresponsiveness to subsequent challenges in the critically ill patient.

Polyphenols and gastrointestinal diseases

Purpose of review This article will review the role of polyphenols in gastrointestinal diseases. Ingested polyphenols are concentrated in the gastrointestinal tract and are not well absorbed into the rest of the body. Thus, the high luminal concentrations achieved support a potential for therapeutic uses in the gastrointestinal tract. Additionally, there is great interest from the general public in complementary and alternative medicine. Recent findings Dietary polyphenols are a major source of antioxidants consumed by humans. Polyphenols possess not only antioxidant properties but also antiviral, antibacterial, antiinflammatory and anticarcinogenic effects, as well as the ability to modulate certain signaling pathways such as nuclear factor-κB activation. Green tea polyphenols have been shown to have efficacy in various models of inflammatory bowel disease. Silymarin, or milk thistle, is hepatoprotective against many forms of experimental liver injury and is widely used in human liver diseases, such as hepatitis C and alcoholic cirrhosis, with an excellent safety profile (but with unclear efficacy). Summary Substantial in-vitro and animal studies support the beneficial effects of polyphenols in many gastrointestinal diseases. Well designed multicenter trials in humans, such as those called for in the 2005 National Institutes of Health Requests for Applications for Silymarin Centers, will be critical for defining the safety, appropriate dosing and therapeutic efficacy of such agents.

Randomized, double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn's disease

Background: Interleukin‐12 (IL‐12) and interleukin‐23 (IL‐23) are inflammatory cytokines linked to the Th‐1 and Th‐17 phenotypes associated with Crohns disease (CD). We investigated the activity and safety of apilimod mesylate (formerly STA‐5326), an oral IL‐12 and IL‐23 inhibitor, in patients with active CD. Methods: We performed a multicenter, Phase 2, randomized, double‐blinded, placebo‐controlled study to evaluate the efficacy of apilimod mesylate in treating 220 adult patients with moderate‐to‐severe CD (Crohns Disease Activity Index [CDAI] score 220–450). Patients were stratified according to C‐reactive protein (CRP) levels and corticosteroid use and were randomly assigned to receive placebo or apilimod mesylate 50 mg daily or 100 mg daily. The study was divided into an induction phase (43 days) and a maintenance phase (125 days). The primary analysis involved a comparison of the proportion of patients experiencing clinical response, defined as at least a 100‐point decrease in CDAI score from baseline at day 29. Data on adverse events were also collected. Results: In all, 220 of the planned 282 patients were enrolled when the Data Monitoring Committee determined that the drug was not efficacious as a treatment and closed enrollment. A clinical response was experienced by 18 patients (24.7%) in the 50‐mg daily (QD) group (n = 73) and 19 patients (25.7%) in the 100 mg QD group (n = 74), as compared with 21 patients (28.8%) in the placebo group (n = 73) on day 29 (P = 0.71 for each comparison). No significant adverse safety signal was observed. Conclusions: Apilimod was well‐tolerated but did not demonstrate efficacy over placebo in patients with active CD. (Inflamm Bowel Dis 2009)

Targeted Drug Delivery to Intestinal Macrophages by Bioactive Nanovesicles Released from Grapefruit

The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food-derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept, we demonstrate that grapefruit-derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS)-induced mouse colitis. These effects were mediated by upregulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1β and TNF-α in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values, and targeting of intestinal macrophages led us to further develop a novel GDN-based oral delivery system. Incorporating methotrexate (MTX), an anti-inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared with free MTX, and remarkably increased its therapeutic effects in DSS-induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis, and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease.

Overview of stem cell therapy for Crohn's disease.

Background: Crohns disease (CD) therapy is rapidly evolving. Recent and ongoing clinical trials using immunologically active stem cells (SC) for the treatment of CD demonstrate the potential for this novel therapy to induce complete and long-lasting remission of symptoms in settings where ‘standard’ therapies have been unsuccessful. Objective/methods: This review of SC, including mesenchymal stem cell (MSC) therapy for CD discusses how the immunological effects of MSC may correct some of the pathophysiological defects underpinning CD, and examines the latest clinical trial data providing evidence of their efficacy in the treatment of Crohns disease. Results/conclusions: Given the beneficial effects on mucosal healing seen in animal models of inflammation and results from early clinical trials, MSC may serve as a candidate therapy for patients who have failed to respond to biological therapy.

A Pilot Study to Evaluate the Safety and Efficacy of an Oral Dose of (−)-Epigallocatechin-3-Gallate–Rich Polyphenon E in Patients With Mild to Moderate Ulcerative Colitis

Background:Green tea and its main polyphenolic component, (−)-epigallocatechin-3-gallate (EGCG), exert powerful anti-inflammatory effects that are protective against both inflammatory diseases and cancer. Research with animal and human cell lines provide plausible support for these claims. Poor absorption results in low systemic bioavailability of EGCG after oral administration but high colonic mucosal exposure. Methods:Patients with mild to moderate ulcerative colitis (UC) were randomized to daily doses of oral Polyphenon E (400 mg or 800 mg of total EGCG daily, administered in split doses) or placebo in a double-blinded, placebo-controlled pilot study. Response was measured by the UC disease activity index and the inflammatory bowel disease questionnaire on day 56. Results:Twenty patients were randomized to active therapy or placebo in a 4:1 ratio. Nineteen subjects received >1 dose of study medication (15 Polyphenon E, 4 placebo). The mean UC disease activity index score at study entry was 6.5 ± 1.9 in the treatment group and 7.3 ± 1.7 in the placebo group. After 56 days of therapy, the response rate was 66.7% (10 of 15) in the Polyphenon E group and 0% (0 of 4) in the placebo group (P = 0.03). The active treatment remission rate was 53.3% (8 of 15) compared with 0% (0 of 4) for placebo (P = 0.10). Polyphenon E treatment resulted in only minor side effects. Conclusions:Administration of Polyphenon E resulted in a therapeutic benefit for patients who were refractory to 5-aminosalicylic and/or azathioprine. This agent holds promise as a novel option for the treatment of patients with UC with mild to moderately active disease.

Relationship between gut microbiota and development of T cell associated disease

The interplay between the immune response and the gut microbiota is complex. Although it is well‐established that the gut microbiota is essential for the proper development of the immune system, recent evidence indicates that the cells of the immune system also influence the composition of the gut microbiota. This interaction can have important consequences for the development of inflammatory diseases, including autoimmune diseases and allergy, and the specific mechanisms by which the gut commensals drive the development of different types of immune responses are beginning to be understood. Furthermore, sex hormones are now thought to play a novel role in this complex relationship, and collaborate with both the gut microbiota and immune system to influence the development of autoimmune disease. In this review, we will focus on recent studies that have transformed our understanding of the importance of the gut microbiota in inflammatory responses.

Overview of biologic therapy for Crohn's disease

Therapy for Crohns disease (CD) is evolving at breakneck speed. Biologic therapies are assuming ever more important roles in treating this unrelenting, life-long disorder. New evidence suggests that earlier, more aggressive use of biological therapies for CD may improve overall efficacy rates, as well as reduce long-term complications. In addition to optimizing the use of older biologic therapies (antibodies against TNF-α), recent and ongoing clinical trials are evaluating the clinical efficacy of a large number of other biologic therapies, honing in on a wide array of immunological targets. The promise of biologic therapies stems from their ability to induce complete and long-lasting remission of symptoms in a way that ‘standard’ therapies have not been able to accomplish. In this review of biologic therapies for CD, we examine the latest clinical trial data and evidence for mechanism of action of a variety of current and future therapies.

Eldelumab [Anti-IP-10] induction therapy for ulcerative colitis: A randomised, placebo-controlled, phase 2b study

BACKGROUND AND AIMS Interferon-γ-inducible protein-10 [IP-10] mediates immune cell trafficking from the circulation to the inflamed colon and decreases gut epithelial cell survival. IP-10 expression is increased in patients with ulcerative colitis [UC]. We report efficacy and safety results from a dose-ranging induction study of eldelumab, a fully human monoclonal antibody to IP-10, in moderately to severely active UC. METHODS A total of 252 adults with UC [Mayo score ≥ 6 and endoscopic subscore ≥ 2] were randomised 1:1:1 to placebo or eldelumab 15 or 25 mg/kg administered intravenously on Days 1 and 8 and every other week thereafter. The primary endpoint was clinical remission [Mayo score ≤ 2; no individual subscale score > 1] at Week 11. Key secondary endpoints included Mayo score clinical response and mucosal healing at Week 11. RESULTS Neither eldelumab 15 or 25 mg/kg resulted in significant increases vs placebo in the proportion of patients achieving Week 11 clinical remission. Remission and response rates were 17.6% and 47.1% with eldelumab 25mg/kg, 13.1% and 44.0% with eldelumab 15mg/kg, and 9.6% and 31.3% with placebo. Clinical remission and response rates were higher in anti-tumour necrosis factor [TNF]-naïve patients treated with eldelumab compared with placebo. Eldelumab treatment was well tolerated and no immunogenicity was observed. CONCLUSIONS The primary endpoint was not achieved with induction treatment with eldelumab 15 or 25 mg/kg in patients with UC. Trends towards clinical remission and response were observed in the overall population and were more pronounced in anti-TNF naïve patients. Eldelumab safety signals were consistent with those reported previously [ClinicalTrials.gov number, NCT01294410].

Accurate and fast 3D colon segmentation in CT colonography

This paper introduces an adaptive level set method for 3D segmentation of colon tissue in CT colonography filled with air and opacified fluid. First, most of the opacified liquid is removed by a threshold value. The closed contours are propagated toward the desired 3D region boundaries through the iterative evolution of the adaptive level sets function. The proposed method has been tested on 22 real CT colonography datasets with various pathologies, and the segmentation accuracy has achieved 98.40%.