Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are immunologically-mediated, debilitating conditions resulting from destructive inflammation of the gastrointestinal tract. The pathogenesis of IBD is incompletely understood, but is considered to be the result of an abnormal immune response with a wide range of cell types and proteins involved. Natural Killer Group 2D (NKG2D) is an activating receptor constitutively expressed on human Natural Killer (NK), γδ T, mucosal-associated invariant T (MAIT), CD56+ T, and CD8+ T cells. Activation of NKG2D triggers cellular proliferation, cytokine production, and target cell killing. Research into the NKG2D mechanism of action has primarily been focused on cancer and viral infections where cytotoxicity evasion is a concern. In human inflammatory bowel disease (IBD) this system is less characterized, but the ligands have been shown to be highly expressed during intestinal inflammation and the following receptor activation may contribute to tissue degeneration. A recent phase II clinical trial showed that an antibody against NKG2D induced clinical remission of CD in some patients, suggesting NKG2D and its ligands to be of importance in the pathogenesis of CD. This review will describe the receptor and its ligands in intestinal tissues and the clinical potential of blocking NKG2D in Crohn’s disease.
Highlights
Crohn’s disease (CD), an inflammatory bowel disease (IBD), is a complex immunologicallymediated chronic illness that is believed to arise due to a dysregulated immune response to microbiota in the gastrointestinal system
This review aims to give an overview of the expression and functional role of the Natural Killer Group 2D (NKG2D) pathway in the healthy and inflamed intestine, as well as the clinical potential of a blocking antibody against the receptor in CD
This study identified an increase of MICA/B+, ULBP1+, and ULBP2+ cells from mucosal infiltrates in tissue sections from active disease only, not when disease was in remission or in normal controls [12]
Summary
Crohn’s disease (CD), an inflammatory bowel disease (IBD), is a complex immunologicallymediated chronic illness that is believed to arise due to a dysregulated immune response to microbiota in the gastrointestinal system. CD is characterized by patchy and transmural inflammation that can occur throughout the gastrointestinal tract, with alternating phases of clinical relapse and remission [1]. Despite newer and better therapies, Crohn’s disease often presents a heavy everyday burden, sometimes leading to surgery and disability [3,4]. The biologic antibodies in clinical development adopt parallel mechanisms of action with the same or other targets, namely blocking of a variety of cytokines, inhibition of the similar protein-dependent migration mechanism or neutralization of chemokines. Other mechanisms may be involved in the pathogenesis of IBD [5,6]
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