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Review
. 2016 Jul;1(2):85-95.
doi: 10.1159/000445986. Epub 2016 Apr 30.

New and Evolving Immunotherapy in Inflammatory Bowel Disease

Mohamad A Raad  1 , Nour H Chams  1 , Ala I Sharara  2
Affiliations
Review

New and Evolving Immunotherapy in Inflammatory Bowel Disease

Mohamad A Raad et al. Inflamm Intest Dis. 2016 Jul.

Abstract

Background: Crohn's disease and ulcerative colitis are chronic inflammatory disorders associated with a dysregulated adaptive and innate immune response to gut commensals in genetically susceptible individuals. The pathogenesis of inflammatory bowel disease is complex, and the disease is characterized by significant phenotypic and genotypic heterogeneity.

Summary: The introduction of anti-TNF biologics has resulted in improved clinical outcomes in patients with severe and moderately severe disease, but the current treatment paradigm continues to depend on systemic immunosuppression (steroids and immunomodulators) and surgical intervention in a significant number of patients, underscoring a significant unmet need. More recently, a number of genetic and immunologic abnormalities have been unraveled including aberrant intestinal mucosal defense function, abnormal intestinal permeability, dysregulated bacterial antigen processing by macrophages and presentation to T cells, cellular immune regulation and signaling, cytokine production, and leukocyte trafficking.

Key messages: Understanding these molecular mechanisms and effector pathways presents an opportunity for the development of new and improved targeted therapies.

Keywords: Biologics; Crohn's disease; Inflammatory bowel disease; Treatment; Ulcerative colitis.

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Figures

Fig. 1
Fig. 1
The currently approved and available IBD therapies include: four anti-TNF agents, namely infliximab, adalimumab, certolizumab pegol, and golimumab, and two anti-integrin agents, natalizumab and vedolizumab. Ustekinumab and MEDI2070 are human monoclonal IgG antibodies that block the receptor of the p40 subunit of the IL-12/23 complex on leukocytes. Etrolizumab is an anti-β7 monoclonal antibody, and tofacitinib is a JAK inhibitor in the JAK/STAT pathway. MAdCAM is a gastrointestinal addressin that binds α4β7 integrins on leukocytes in the leukocyte recruitment process. DC = Dendritic cell; M = microfold cell; TREG cell = regulatory T cells. Reproduced with permission from Danese et al. [83].
Fig. 2
Fig. 2
SMAD pathway. a TGF-β1 binds to the type II receptor to activate the type I receptor. The activated type I receptor phosphorylates Smad2/3 which, once phosphorylated, interact with Smad4 to form the Smad2/3/Smad4 complex. The complex migrates to the nucleus to bind to DNA and activate transcription. b The phosphorylation of Smad3 is prevented through the interaction of Smad7, a TGF-β1 type I receptor inhibitor, that binds to and blocks the TGF-β1-associated Smad signaling pathway shown in a. Reproduced with permission from Monteleone et al. [84].
See this image and copyright information in PMC

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