Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

McCarthy, Neil E.; Hedin, Charlotte; Sanders, Theodore J.; Amon, Protima; Hoti, Inva; Ayada, Ibrahim; Baji, Vidya; Giles, Edward; Wildemann, Martha; Bashir, Zora; Whelan, Kevin; Sanderson, Ian R.; Lindsay, James O.; Stagg, Andrew J.

doi:10.1172/jci80840

Cited by 40 publications

(32 citation statements)

References 54 publications

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“…As for VD2 T-cells, which are not MHC-restricted T-cells 42,43 , we showed a general decrease in the periphery with disease severity. This is in line with other inflammatory disease such as psoriasis 44 and Crohn’s disease 45 . However, in the lungs, during chronic obstructive pulmonary disease, γδ T-cell counts have been reported to be significantly lower in induced sputum (IS) and bronchoalveolar lavage (BAL) but not in peripheral blood, suggesting unclear inflammatory mechanisms that could influence γδ T-cells counts in the periphery 46 .…”

Section: Discussionsupporting

confidence: 84%

“…Our results indicate that an early post illness onset iNVD2R, accessible through a simple 5 colours flow cytometry panel (CD3; VD2; CD66b/CD15; CD10; CD45), would be an excellent prognostic screening tool for predicting probable patient progression to pneumonia or hypoxia. Moreover, CD8 could also be included in the flow cytometry panel as a fallback option since VD2 counts could be decreased by medication, such as Azathioprine, as well as underlying conditions, such as inflammatory bowel disease, aging or psoriasis, which could be risk factors for COVID-19 45 . Analysis of the proposed parameter would allow for a more accurate and earlier prognosis due to the interconnection between neutrophils and Vδ2 T cells, which can then be utilised for early therapeutic interventions, improve patient triage and better healthcare resource management.…”

Section: Discussionmentioning

confidence: 99%

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Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19

Carissimo

Kwok

et al. 2020

Preprint

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39SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 40 pandemic. Severe complications are observed only in a small proportion of infected 41 patients but the cellular mechanisms underlying this progression are still unknown. 42Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients 43 revealed a dramatic increase in the number of immature neutrophils. This increase 44 strongly correlated with disease severity and was associated with elevated IL-6 and 45 IP-10 levels, two key players in the cytokine storm. The most pronounced decrease 46 in cell counts was observed for CD8 T-cells and VD2 γδ T-cells, which both exhibited 47 increased differentiation and activation. ROC analysis revealed that the count ratio of 48 immature neutrophils to CD8 or VD2 T-cells predicts pneumonia onset (0.9071) as 49 well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a 50 useful prognostic marker for preventive patient management and improved 51 healthcare resource management. 52

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19

Carissimo

Kwok

et al. 2020

Preprint

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show abstract

“…[114, 115] Interestingly, azathioprine (AZA) treatment selectively depletes this subtype in Crohn’s disease patients. [116] Although the mechanism by which AZA reduces Vδ2 + T cell number has yet to be determined, this effect could not be attributed solely to impaired purine biosynthesis since similar results were not observed in patients treated with methotrexate. [116] However, its effect on Vδ1 + T cells, which constitute the majority of human γδ IELs, remains unclear.…”

Section: Addressing the Differences Between Mice And Men: γδ Iels In Ibdmentioning

confidence: 99%

“…[116] Although the mechanism by which AZA reduces Vδ2 + T cell number has yet to be determined, this effect could not be attributed solely to impaired purine biosynthesis since similar results were not observed in patients treated with methotrexate. [116] However, its effect on Vδ1 + T cells, which constitute the majority of human γδ IELs, remains unclear. These CD8 + Vδ1 + cells display a cytotoxic Th1 phenotype and produce IFNγ similar to murine γδ IELs.…”

Section: Addressing the Differences Between Mice And Men: γδ Iels In Ibdmentioning

confidence: 99%

Sentinels at the Frontline: the Role of Intraepithelial Lymphocytes in Inflammatory Bowel Disease

Edelblum

2017

Curr Pharmacol Rep

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Purpose of review Intestinal mucosal immunity is tightly regulated to ensure effective host defense against invasive microorganisms while limiting the potential for aberrant damage. In inflammatory bowel disease (IBD), an imbalance between effector and regulatory T cell populations results in an uncontrolled inflammatory response to commensal bacteria. Intraepithelial lymphocytes (IEL) are perfectly positioned within the intestinal epithelium to provide the first line of mucosal defense against luminal microbes or rapidly respond to epithelial injury. This review will highlight how IELs promote protective intestinal immunity and discuss the evidence indicating that altered IEL responses contribute to the pathogenesis of IBD. Recent findings Although the role of IELs in mucosal homeostasis has been largely underappreciated, many of the same factors that contribute to the dysregulation of host defense in IBD also adversely affect IELs. For example, IL-23 and the endoplasmic reticulum stress response can enhance IEL lytic activity toward enterocytes. Microbial dysbiosis or defective microbial recognition results in the loss of regulatory IELs, further amplifying these pro-inflammatory effects. Migration of T cells into or within the intraepithelial compartment has a profound effect on their differentiation or effector function demonstrating that IELs are exquisitely sensitive to changes in the local intestinal microenvironment. Summary Enhanced mechanistic insight into the regulation of IEL survival, differentiation and effector function may provide useful tools to modulate IEL surveillance or enhance IEL regulatory function. Elucidation of these processes may result in the development of novel therapeutics to reduce intestinal inflammation and reinforce the mucosal barrier in IBD.

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“…Vδ2+ T cells are known to produce TNF-α, IFN-γ, and granzyme, are abundant in gut tissue, especially in patients with IBD 7,8,9 , and are responsive to bacterial phosphoantigens through the atypical activating molecule CD277 (butyrophilin-3). Antigenic stimulation can cause a robust expansion of Vδ2+ T cells, which is self-limiting 9 .…”

Section: Lettermentioning

confidence: 99%

Gamma Delta T Cell Subset V Gamma 2+ Expansion Associated with Longterm Infliximab Treatment in a Patient with Ankylosing Spondylitis

2016

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Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

Cited by 40 publications

References 54 publications

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19

Sentinels at the Frontline: the Role of Intraepithelial Lymphocytes in Inflammatory Bowel Disease

Gamma Delta T Cell Subset V Gamma 2+ Expansion Associated with Longterm Infliximab Treatment in a Patient with Ankylosing Spondylitis

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