Inhibition of the kinase ITK in a mouse model of asthma reduces cell death and fails to inhibit the inflammatory response

Sun, Yonglian; Peng, Ivan; Webster, Joshua D.; Suto, Eric; Lesch, Justin; Wu, Xiumin; Senger, Kate; Francis, George; Barrett, Kathy; Collier, Jenna L.; Burch, Jason D.; Zhou, Meijuan; Chen, Yuan; Chan, Connie; Eastham-Anderson, Jeff; Ngu, Hai; Li, Olga; Staton, Tracy; Havnar, Charles; Jaochico, Allan; Jackman, Janet; Jeet, Surinder; Riol-Blanco, Lorena; Wu, Lawren C.; Choy, David F.; Arron, Joseph R.; McKenzie, Brent; Ghilardi, Nico; Ismaili, Moulay Hicham Alaoui; Pei, Zhonghua; DeVoss, Jason; Austin, Cary D.; Lee, Wyne P.; Zarrin, Ali A.

doi:10.1126/scisignal.aab0949

Cited by 38 publications

(55 citation statements)

References 55 publications

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“…This T cell expansion is unlikely to be caused by BTK inhibition, as we did not observe increased T cell numbers in patients treated with the more selective BTK inhibitor acalabrutinib that lacks ITK inhibitory activity. While discerning the mechanism of T cell expansion in vivo in CLL patients is not possible, we provide evidence that ibrutinib treatment of activated T cells diminishes AICD by targeting ITK, a finding also reported in murine models of ITK deficiency (29). ITK has been demonstrated to be involved in TCR-induced upregulation of FASL and AICD of T cells (28,29).…”

Section: Ibrutinib Downregulates Immunosuppressive Molecules Cd200mentioning

confidence: 54%

“…While discerning the mechanism of T cell expansion in vivo in CLL patients is not possible, we provide evidence that ibrutinib treatment of activated T cells diminishes AICD by targeting ITK, a finding also reported in murine models of ITK deficiency (29). ITK has been demonstrated to be involved in TCR-induced upregulation of FASL and AICD of T cells (28,29). In vitro, ITK-deficient T cells have been found to have impaired proliferation (41), whereas in vivo, activated ITK -/-T cells survived to a much greater degree than normal T cells, leading to a greater accumulation (28).…”

Section: Ibrutinib Downregulates Immunosuppressive Molecules Cd200mentioning

confidence: 55%

“…However, we found no significant change in circulating T cell numbers before and after ibrutinib treatment, as shown in Supplemental Figure 7. Furthermore, we went on to question if ibrutinib can enhance the expansion of activated antigen-specific T cells using a mouse leu- AICD by reducing the upregulation of FASL (29). Here, we found that the upregulation of FASL expression in activated T cells after restimulation was indeed decreased by ibrutinib treatment (Supplemental Figure 2C), suggesting that ibrutinib ameliorates AICD by decreasing TCR activation-induced FASL upregulation.…”

Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 59%

“…Therefore, we investigated if acalabrutinib (Supplemental Figure 1B). Given that activated ITKdeficient T cells in murine systems have diminished activationinduced cell death (AICD) (28,29), we hypothesized that the ITK inhibitory activity of ibrutinib, but not acalabrutinib, may explain this observation. We therefore examined the influence of these 2 agents on T cells ex vivo with extended activation.…”

Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 99%

“…Targeting ITK with kinase inhibitors showed a similar pattern. In vitro, ITK inhibitors inhibit IL-2 secretion and T cell proliferation (42), whereas in vivo the ITK inhibitor was found to reduce AICD, leading to a 2-to 3-fold increase in activated T cell numbers (29).…”

Section: Ibrutinib Downregulates Immunosuppressive Molecules Cd200mentioning

confidence: 99%

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Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

313

343

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BACKGROUND.Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS.Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8 + T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4 + T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025.

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Section: Ibrutinib Downregulates Immunosuppressive Molecules Cd200mentioning

confidence: 54%

Section: Ibrutinib Downregulates Immunosuppressive Molecules Cd200mentioning

confidence: 55%

Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 59%

Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 99%

Section: Ibrutinib Downregulates Immunosuppressive Molecules Cd200mentioning

confidence: 99%

See 3 more Smart Citations

Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

313

343

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Increased expression of CSF1 in patients with eosinophilic asthma

Tang

Xiao

et al. 2023

Immunity Inflam & Disease

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Background The link between colony‐stimulating factor 1 (CSF1) and asthma was reported recently. However, the role and mechanism of CSF1 in asthma remain poorly understood. In this study, we aimed to explore the expression and its potential mechanism of CSF1 in asthma. Methods CSF1 expression in the airway samples from asthmatics and healthy controls were examined, then the correlations between CSF1 and eosinophilic indicators were analyzed. Subsequently, bronchial epithelial cells (BEAS‐2B) with CSF1 overexpression and knockdown were constructed to investigate the potential molecular mechanism of CSF1. Finally, the effect of CSF1R inhibitor on STAT1 was investigated. Results The expression of CSF1 was significantly increased in patients with asthma compared to healthy controls, especially in patients with severe and eosinophilic asthma. Upregulated CSF1 positively correlated with airway‐increased eosinophil inflammation. In vitro, cytokines interleukin 13 (IL‐13) and IL‐33 can stimulate the upregulation of CSF1 expression. CSF1 overexpression enhanced p‐CSF1R/CSF1R and p‐STAT1/STAT1 expression, while knockdown CSF1 using anti‐CSF1 siRNAs decreased p‐CSF1R/CSF1R and p‐STAT1/STAT1 expression. Furthermore, the inhibitor of CSF1R significantly decreased p‐STAT1/STAT1 expression. Conclusions Sputum CSF1 may be involved in asthmatic airway eosinophil inflammation by interacting with CSF1R and further activating the STAT1 signaling. Interfering this potential pathway could serve as an anti‐inflammatory therapy for asthma.

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BTK/ITK dual inhibitors: Modulating immunopathology and lymphopenia for COVID-19 therapy

McGee

August

Huang

2020

Journal of Leukocyte Biology

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Bruton's tyrosine kinase (BTK) signaling is involved in innate immune responses and regulates the production of proinflammatory cytokines that can contribute to COVID-19 immunopathology. Clinical trials with BTK inhibitors in COVID-19 treatment have been proposed, and previous studies have attempted to investigate the therapeutic effects of ibrutinib and underlying mechanisms in treating viral pneumonia. These attempts, however, did not consider potential off target effect of BTK inhibitors on T cell differentiation, function, and survival, which may be beneficial in treatment for COVID-19. Here, we summarize the current knowledge of BTK/IL-2-inducible T-cell kinase (ITK) signaling in immunopathology and lymphopenia and discuss the potential of BTK/ITK dual inhibitors such as ibrutinib in modulating immunopathology and lymphopenia, for COVID-19 therapy.

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Inhibition of the kinase ITK in a mouse model of asthma reduces cell death and fails to inhibit the inflammatory response

Cited by 38 publications

References 55 publications

Ibrutinib treatment improves T cell number and function in CLL patients

Ibrutinib treatment improves T cell number and function in CLL patients

Increased expression of CSF1 in patients with eosinophilic asthma

BTK/ITK dual inhibitors: Modulating immunopathology and lymphopenia for COVID-19 therapy

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