Biological Therapies of Inflammatory Bowel Disease

Aiping Bai; Zhikang Peng

Disclosures

Immunotherapy. 2010;2(5):727-742. 

In This Article

Abstract and Introduction

Abstract

Inflammatory bowel disease (IBD) is characterized by increasing morbidity and, if suboptimally treated, poor prognosis. Recent evidence strongly suggests that dysfunctional immune responses play an important role in the pathogenesis of IBD. Therefore, immunologically downregulating the overactivated innate and adaptive immune responses may be a better approach to treat IBD than currently used pharmaceutical therapies. In recent years, many new biological therapies have been developed. These therapies are shown to be effective for inducing remission, preventing complications, improving life quality of the patients, and reducing hospitalization and surgical rates. This article introduces and discusses these new biological agents that have been used effectively in clinic for IBD patients.

Introduction

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a lifelong disease occurring early in life. The incidence and prevalence of IBD markedly increased in recent years, and IBD is considered to be one of the most prevalent gastrointestinal diseases.[1,2] Estimates indicate that IBD affected approximately 1.0–1.5 million Americans,[3] and approximately 10–15% of IBD patients present later in life. Recent estimates from a population-based, multiple province-wide study in Canada indicate that approximately 0.5% of Canadians have IBD, and incidence rates across the country are among the highest in the world.[4]

Although the etiology of IBD remains unclear, it is strongly suggested that dysregulated immune responses play an important role in the development of IBD.[5] After exposure to the abundant intestinal bacterial antigens or environmental factors, innate immune cells such as dendritic cells and macrophages in intestinal mucosa are activated, leading to the overproduction of chemokines and proinflammatory cytokines such as TNF, IL-12 and IL-23.[6,7] Innate immune cells, together with these proinflammatory cytokines, including IL-12 and IL-23, stimulate T-helper (Th) cell activation and differentiation into Th1 cells and IL-17-producing Th17 cells.[8] Both of these T cells are highly expressed in the inflamed mucosa of IBD patients.[9,10] Meanwhile, these cytokines induce the expression of adhesion molecule receptors in endothelial cells, which together with chemokines, further initiate leukocyte migration to sites of inflammation.[11] Thus, the aggregated leukocytes and cytokines contribute in maintaining the uncontrolled inflammatory response, eventually leading to the intestinal tissue damage found in IBD.[12,13] Downregulating overactivated innate and adaptive immune responses can successfully ameliorate IBD, as indicated by clinical and experimental research.[14–17]

Current nonsurgical treatments of IBD mainly include the administration of corticosteroids, 5-aminosalicylic acid (5-ASA) preparations, and immune-suppressive drugs such as azathioprine. However, only 50% of patients achieve sustained remission with these drugs and the treatment may cause many side effects, including the well-known toxicity of corticosteroids and cytopenia caused by azathioprine.[18,19] Recently, biological therapies that target immune pathways have been emerged as a new and effective therapeutic approach for the treatment of immune dysfunction-mediated diseases. They include administration of monoclonal antibodies (mAbs) against cytokines and those that influence immune responses such as certain small molecules, helminth ova and stem cells. As IBD is an immunological disease, biological therapy targeting excessive cytokines and immune responses in inflamed mucosa should be a highly promising approach to treatment. To date, many new biological agents acting as therapeutic modifiers have emerged as important new treatments. Here we introduce these new biological agents that have been used effectively in clinic for IBD patients (Table 1).

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