NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration

Vadstrup, Kasper; Galsgaard, Elisabeth D.; Jensen, Hans Grinsted; Lanier, Lewis L.; Ryan, James C.; Chen, Shih‐Yu; Nolan, Garry P.; Vester‐Andersen, Morten; Pedersen, Julie Steen; Gerwien, Jens; Jensen, Teis; Bendtsen, Flemming

doi:10.1016/j.yexmp.2017.06.010

Cited by 16 publications

(28 citation statements)

References 64 publications

(75 reference statements)

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“…The degree of inflammation in CD patients proved to correlate inversely with the amounts of γδ T cells and CD56 + cells expressing NKG2D. In vitro inflammatory stimuli were shown to induce ligand expression on human intestinal microvascular endothelial cells and ligand expression was found to augment the migration of CD8 + NKG2D + T cells …”

Section: Functional Roles Of Nkg2d and Its Ligands In Diseasementioning

confidence: 97%

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NKG2D‐ligands: Putting everything under the same umbrella can be misleading

Campos-Silva

Kramer

Valés‐Gómez

2018

HLA

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NKG2D is a key receptor for the activation of immune effector cells, mainly Natural Killer cells and T lymphocytes, in infection, cancer and autoimmune diseases. Since the detection of ligands for NKG2D in sera of cancer patients is, in many human models, indicative of prognosis, a large number of studies have been undertaken to improve understanding of the biology regulating this receptor and its ligands, with the aim of translating this knowledge into clinical practice. Although it is becoming clear that the NKG2D system can be used as a tool for diagnosis and manipulated for therapy, some questions remain open due to the complexity associated with the existence of a large number of ligands, each one of them displaying distinct biological properties. In this review, we have highlighted some key aspects of this system that differ between humans and mice, including the properties of NKG2D, as well as the genetic and biochemical complexity of NKG2D-ligands. All of these features affect the characteristics of the immune response exerted by NKG2D-expressing cells and are likely to be important factors in the clearance of a tumour or the development of autoimmunity. Implementation of more global analyses, including information on genotype, transcription and protein properties (cellular vs released to the blood stream) of NKG2D-ligands expressed in patients will be necessary to fully understand the links between this system and disease progression.

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Section: Functional Roles Of Nkg2d and Its Ligands In Diseasementioning

confidence: 97%

“…In vitro inflammatory stimuli were shown to induce ligand expression on human intestinal microvascular endothelial cells and ligand expression was found to augment the migration of CD8 + NKG2D + T cells. 131…”

Section: Crohn's Diseasementioning

confidence: 99%

NKG2D‐ligands: Putting everything under the same umbrella can be misleading

Campos-Silva

Kramer

Valés‐Gómez

2018

HLA

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“…NKG2D is expressed to a high degree on NK and CD8 + T cells in CD also, but can also be detected on CD4 + T cells in inflamed CD intestine [ 7 , 73 ]. The expression level on CD4 + T cells have been shown to increase with Crohn’s disease in the lamina propria compared with controls and patients with ulcerative colitis.…”

Section: Nkg2d In Crohn’s Diseasementioning

confidence: 99%

“…This might be connected to the finding that NKG2D expression on γδ T cells also correlates negatively to the cells production of GM-CSF, but positively to the release of IL-10, both measured on the protein level. The expression level of NKG2D on CD56 + T cells correlate to the two cytokines in the complete opposite way, which implies that pro- and anti-inflammatory cytokines influence the NKG2D molecular pathway [ 73 ]. Notably, γδ T cells constitute ~40% of the intraepithelial lymphocytes (IEL) [ 82 , 83 ], and might have a protective role in IBD [ 84 ].…”

Section: Nkg2d In Crohn’s Diseasementioning

confidence: 99%

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Anti-NKG2D mAb: A New Treatment for Crohn’s Disease?

Vadstrup

Bendtsen

2017

IJMS

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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.

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Model‐Based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti–Natural Killer Group 2 Member D Monoclonal Antibody, in Moderately to Severely Active Crohn Disease

Zhou

Chen

et al. 2023

The Journal of Clinical Pharma

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Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevents the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double-blind, placebo-controlled trial in patients with moderately to severely active Crohn disease (CD). While the proof-of-concept part I of the study demonstrated significant treatment effects,part II (dose-ranging) revealed an unexpected lack of dose-response and a modest degree of clinical benefit for treatment groups. To inform further drug development, population pharmacokinetic (PopPK) modeling and exposure-response (E-R) analyses were planned and performed. A 1-compartment PopPK model with first-order absorption and parallel linear and nonlinear elimination pathways was established for tesnatilimab in patients with CD. No clinically significant covariates were identified, and overall consistent pharmacokinetics were observed between part I and part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood natural killer group 2 member D receptors and target engagement at all tested dose levels. Pooled part I and part II data showed a positive efficacy E-R relationship; however, this was driven by data from part I. Part II-only analysis did not show an apparent efficacy E-R relationship. No important covariates were identified in efficacy E-R analyses, overall, and in various subpopulations. No apparent E-R relationships were observed for the investigated safety end points. The PopPK and E-R analyses indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement.

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NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration

Cited by 16 publications

References 64 publications

NKG2D‐ligands: Putting everything under the same umbrella can be misleading

NKG2D‐ligands: Putting everything under the same umbrella can be misleading

Anti-NKG2D mAb: A New Treatment for Crohn’s Disease?

Model‐Based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti–Natural Killer Group 2 Member D Monoclonal Antibody, in Moderately to Severely Active Crohn Disease

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