Cytokine Blockade in Inflammatory Bowel Diseases

Abstract

Inflammatory bowel diseases (IBDs) are chronic disabling diseases with significant morbidity. A deregulated immune response towards the intestinal microbiota is thought to play an important role in the pathogenesis of IBD, and thus biological therapies targeting key molecules such as cytokines have been designed. Several anti-TNF-α agents are currently being used to treat Crohn's disease and ulcerative colitis. Although these molecules dramatically improved the treatment of patients, side effects and the development of antidrug antibodies limits their application. There is thus an urgent need for alternative approaches to decrease inflammation and limit immunogenicity. Small neutralizing molecules, active immunization, gene silencing, selective transcription inhibitors and delivery of agents through the oral route are some of the currently developed strategies to meet these needs. In parallel, neutralizing antibodies targeting other pathways of the immune system have been developed and tested. Antibodies targeting IL-12/IL-23 pathways, and proinflammatory cytokines such as IFN-γ, IL-17A, IL-2 and IL-6 often showed an initial promising result, but for none of these agents efficacy has unequivocally been established. Administration of the regulatory cytokines IL-10 and IL-11 also failed to induce reproducible clinical effects. This article focuses on the anti-TNF therapies and the current challenges with monoclonal antibody therapies, discusses the innovative strategies targeting cytokine pathways to decrease inflammation in the bowel, and summarizes the recently developed agents neutralizing proinflammatory cytokines.

Protective Effect ofAmphipterygium adstringensExtract on Dextran Sulphate Sodium-Induced Ulcerative Colitis in Mice

“…The increased proinflammatory cytokines such as TNF- α , IFN- γ , and IL-1 β amplify the inflammatory cascade and result in intestinal tissue damage in UC induced by DSS [32]. Among those cytokines, the overexpression of TNF- α is vital in intestinal mucosal impairment [33].…”

Hydroxylases as therapeutic targets in inflammatory bowel disease

“…The treatment of IBD has more recently been revolutionized by the development of targeted molecular agents with the use of therapeutic antibodies against TNFalpha (anti-TNF) to suppress mucosal inflammation. 17,18 The step-up approach for the treatment of IBD has been challenged with the emergence of such 'biologic' agents and a 'top-down' therapeutic paradigm has been proposed, which advocates early aggressive use of therapeutic antibodies as a first line of treatment. 19 However, early use of therapeutic antibodies, typically combined with immunomodulators to promote mucosal healing may also lead to increased risk of toxicity, infections and the rare risk of hepatosplenic T-cell lymphoma in young men.…”

Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer

“…Although the pathogenesis of IBD remains unclear, a number of studies have suggested the involvement of abnormal apoptosis in intestinal epithelial cells, resulting from increased production of cytokines, such as TNF, ILs, and IFNs (2). TNFa is a key mediator of inflammation in IBD and has been the primary target of biologic therapies (3). This cytokine induces inflammation by promoting the production of IL1b and IL6, expression of adhesion molecules, proliferation of fibroblasts, activation of procoagulant factors, and cytotoxicity of the acute phase response (4).…”