Inhibition of the IL-2-inducible tyrosine kinase (Itk) activity: a new concept for the therapy of inflammatory skin diseases

Bonin, Arne von; Rausch, Alexandra; Mengel, Anne; Hitchcock, Marion; Krüger, Melanie; Ahsen, Oliver von; Merz, Claudia; Röse, Lars; Stock, Christine; Martin, Stefan F.; Leder, Gabriele; Döcke, Wolf‐Dietrich; Asadullah, Khusru; Zügel, Ulrich

doi:10.1111/j.1600-0625.2010.01198.x

Cited by 35 publications

(24 citation statements)

References 59 publications

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“…Itk −/− mice show reduced levels of IL-4 and IL-13 but not IFNγ (mRNA and protein) as measured in the lungs of Itk knockout mice compared to wild type mice (WT) [27], [28] and this effect was accompanied by a significant reduction in the Th2 promoting transcription factor GATA3 [27]. Furthermore, Itk −/− mice showed a reduced response in a model of atopic dermatitis [29]. In human studies, genetic analysis has shown SNPs in Itk are associated with atopy, allergic rhinitis and asthma [30], [31].…”

Section: Discussionmentioning

confidence: 99%

“…ITK mRNA levels in the peripheral blood T cells is elevated in atopic dermatitis patients compared to healthy controls, and this increase correlates with disease severity [44]. Furthermore, ITK expression is increased in lesional skin from patients with atopic dermatitis and allergic contact dermatitis [29]. Itk −/− mice show significantly reduced inflammation in models of contact hypersensitivity, and this anti-inflammatory effect was reproduced by systemic administration of an ITK inhibitor [29].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, ITK expression is increased in lesional skin from patients with atopic dermatitis and allergic contact dermatitis [29]. Itk −/− mice show significantly reduced inflammation in models of contact hypersensitivity, and this anti-inflammatory effect was reproduced by systemic administration of an ITK inhibitor [29].…”

Section: Discussionmentioning

confidence: 99%

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Characterisation of a K390R ITK Kinase Dead Transgenic Mouse – Implications for ITK as a Therapeutic Target

Deakin

Wilson

et al. 2014

PLoS ONE

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Interleukin-2 inducible tyrosine kinase (ITK) is expressed in T cells and plays a critical role in signalling through the T cell receptor. Evidence, mainly from knockout mice, has suggested that ITK plays a particularly important function in Th2 cells and this has prompted significant efforts to discover ITK inhibitors for the treatment of allergic disease. However, ITK is known to have functions outside of its kinase domain and in general kinase knockouts are often not good models for the behaviour of small molecule inhibitors. Consequently we have developed a transgenic mouse where the wild type Itk allele has been replaced by a kinase dead Itk allele containing an inactivating K390R point mutation (Itk-KD mice). We have characterised the immune phenotype of these naive mice and their responses to airway inflammation. Unlike Itk knockout (Itk−/−) mice, T-cells from Itk-KD mice can polymerise actin in response to CD3 activation. The lymph nodes from Itk-KD mice showed more prominent germinal centres than wild type mice and serum antibody levels were significantly abnormal. Unlike the Itk−/−, γδ T cells in the spleens of the Itk-KD mice had an impaired ability to secrete Th2 cytokines in response to anti-CD3 stimulation whilst the expression of ICOS was not significantly different to wild type. However ICOS expression is markedly increased on αβCD3+ cells from the spleens of naïve Itk-KD compared to WT mice. The Itk-KD mice were largely protected from inflammatory symptoms in an Ovalbumin model of airway inflammation. Consequently, our studies have revealed many similarities but some differences between Itk−/−and Itk-KD transgenic mice. The abnormal antibody response and enhanced ICOS expression on CD3+ cells has implications for the consideration of ITK as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Characterisation of a K390R ITK Kinase Dead Transgenic Mouse – Implications for ITK as a Therapeutic Target

Deakin

Wilson

et al. 2014

PLoS ONE

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“…Nevertheless, a few mediators of T H 9 driven inflammation in atopic dermatitis have been identified. For instance, Itk, a mediator of T cell receptor signaling and a positive regulator of T H 9 differentiation has been shown to be expressed in T cells in lesional skin of AD but not in psoriasis [48, 49]. As for the downstream effects of IL-9 in atopic dermatitis, similar considerations can be made as have been outlined above for their role in skin infection (Fig.…”

Section: Th9 Cells In Skin Disordersmentioning

confidence: 97%

TH9 cells in skin disorders

Clark

Schlapbach

2016

Semin Immunopathol

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Interleukin 9 secreting TH9 cells have been proposed as the latest addition to the family of T helper cell subsets. While a growing body of evidence from animal models points to important roles for these cells in allergic inflammation of the lung, autoinflammation of the gastrointestinal tract, and tumor immunity, their role in skin immunity and skin immunopathology remains poorly defined. Interestingly, studies of T helper cells from healthy humans suggest that TH9 cells are predominantly skin-homing and skin-resident and that they are involved in protection against extracellular pathogens. Thus, TH9 cells have entered the stage as potential mediators of cutaneous pathology. However, under which conditions and by which mechanisms these cells contribute to skin immunity and disease still has to be investigated. Here, we review our current understanding of TH9 cells as skin-tropic T helper cells and their involvement in skin pathology. Further, we discuss open questions with regard to the intricate nature of interleukin 9 producing T helper cells.

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“…Itk plays an important role in transmitting signals at the immunological synapse, Itk (Ϫ/Ϫ) cells had severe reduction of IL-2 and IFN-␥ secretion (Schaeffer et al, 1999;von Bonin et al, 2011). After incubation of Jurkat cells with 0.5 M CTA056, the mRNA levels of IL-2 and IFN-␥ were measured using real-time PCR, and the IL-2 and IFN-␥ secretions were measured using an ELISA assay.…”

Section: Cta056 Inhibits the Formation Of Phospho-itk In Jurkat Cellsmentioning

confidence: 99%

Molecular Characteristics of CTA056, a Novel Interleukin-2-Inducible T-Cell Kinase Inhibitor that Selectively Targets Malignant T Cells and Modulates Oncomirs

et al. 2012

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Interleukin-2-inducible T-cell kinase (Itk) is a member of the Btk (Bruton's tyrosine kinase) family of tyrosine kinases. Itk plays an important role in normal T-cell functions and in the pathophysiology of both autoimmune diseases and T-cell malignancies. Here, we describe the initial characterization of a selective inhibitor, 7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one (CTA056), that was developed through screening a 9600-compound combinatorial solution phase library, followed by molecular modeling, and extensive structure-activity relationship studies. CTA056 exhibits the highest inhibitory effects toward Itk, followed by Btk and endothelial and epithelial tyrosine kinase. Among the 41 cancer cell lines analyzed, CTA056 selectively targets acute lymphoblastic T-cell leukemia and cutaneous T-cell lymphoma. Normal T cells are minimally affected. Incubation of Jurkat and MOLT-4 cells with CTA056 resulted in the inhibition of the phosphorylation of Itk and its effectors including PLC-␥, Akt, and extracellular signal-regulated kinase, as well as the decreased secretion of targeted genes such as interleukin-2 and interferon-␥. Jurkat cells also underwent apoptosis in a dose-dependent manner when incubated with CTA056. The potent apoptosis-inducing potential of CTA056 is reflected by the significant modulation of microRNAs involved in survival pathways and oncogenesis. The in vitro cytotoxic effect on malignant T cells is further validated in a xenograft model. The selective expression and activation of Itk in malignant T cells, as well as the specificity of CTA056 for Itk, make this molecule a potential therapeutic agent for the treatment of T-cell leukemia and lymphoma.

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Inhibition of the IL-2-inducible tyrosine kinase (Itk) activity: a new concept for the therapy of inflammatory skin diseases

Cited by 35 publications

References 59 publications

Characterisation of a K390R ITK Kinase Dead Transgenic Mouse – Implications for ITK as a Therapeutic Target

Characterisation of a K390R ITK Kinase Dead Transgenic Mouse – Implications for ITK as a Therapeutic Target

TH9 cells in skin disorders

Molecular Characteristics of CTA056, a Novel Interleukin-2-Inducible T-Cell Kinase Inhibitor that Selectively Targets Malignant T Cells and Modulates Oncomirs

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