Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK

Immunology Research Laboratories and Department of Veterinary Science, Pennsylvania State University, University Park, PA 16802, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2003; 170(10):5056-63. DOI: 10.4049/jimmunol.170.10.5056
Source: PubMed


Allergic asthma patients manifest airway inflammation and some show increases in eosinophils, T(H)2 cells, and cytokines, increased mucous production in the lung, and elevated serum IgE. This T(H)2-type response suggests a prominent role for T(H)2 cells and their cytokines in the pathology of this disease. The Tec family nonreceptor tyrosine kinase inducible T cell kinase (ITK) has been shown to play a role in the differentiation and/or function of T(H)2-type cells, suggesting that ITK may represent a good target for the control of asthma. Using a murine model of allergic asthma, we show here that ITK is involved in the development of immunological symptoms seen in this model. We show that mice lacking ITK have drastically reduced lung inflammation, eosinophil infiltration, and mucous production following induction of allergic asthma. Notably, T cell influx into the lung was reduced in mice lacking ITK. T cells from ITK(-/-) mice also exhibited reduced proliferation and cytokine secretion, in particular IL-5 and IL-13, in response to challenge with the allergen OVA, despite elevated levels of total IgE and increased OVA-specific IgE responses. Our results suggest that the tyrosine kinase ITK preferentially regulates the secretion of the T(H)2 cytokines IL-5 and IL-13 and may be an attractive target for antiasthmatic drugs.

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    • "Itk−/− mice fail to clear Nippostrongylus brasiliensis and Schistosoma mansoni infection due to a failure to mount an effective Th2 response [17], [19]. Further evidence for defective Th2 immunity is that Itk−/− mice are resistant to developing airway inflammation and hyperreactivity in response to ovalbumin (OVA) sensitisation and challenge [26]–[28]. Ex-vivo activation of CD4+ cells isolated from draining lymph nodes of OVA sensitised mice showed complete inhibition of IL-5 and IL-13, but partial reduction in IFNγ and IL-10 [26]. 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]. "
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    ABSTRACT: 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.
    PLoS ONE 09/2014; 9(9):e107490. DOI:10.1371/journal.pone.0107490 · 3.23 Impact Factor
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    • "Other data suggest that Itk and Txk play a divergent role in T cell differentiation. Itk -/- mice are unable to mount a Th2 response in models of allergic asthma [14], as well as following infection with Leishmania major, Nippostrongylus brasiliensis, and Schistosoma Mansoni, which lead to Th1 cytokine production [15,16]. Surprisingly Itk -/- Txk -/- mice mount Th2 responses, which possibly suggests that these Tec kinases are involved in Th1/Th2 polarization. "
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    ABSTRACT: Background Glucocorticoids affect peripheral immune responses, including modulation of T-cell activation, differentiation, and apoptosis. The quantity and quality of T-cell receptor (TCR)-triggered intracellular signals modulate T-cell function. Thus, glucocorticoids may affect T cells by interfering with the TCR signaling cascade. The purpose of the study was to search for glucocorticoid-modulated kinases downstream of the TCR. Methods Gene modulation in lymphoid cells either treated with glucocorticoids or from glucocorticoid-treated mice was studied using a RNase protection assay, real-time PCR, and western blotting. The sensitivity of genetically modified thymocytes to glucocorticoid-induced apoptosis was studied by performing hypotonic propidium iodide staining and flow cytometry. The Student’s t-test was employed for statistical evaluation. Results We found that transcription of Itk, a non-receptor tyrosine kinase of the Tec family, was up-regulated in a mouse T-cell hybridoma by the synthetic glucocorticoid dexamethasone. In contrast, dexamethasone down-regulated the expression of Txk, a Tec kinase that functions redundantly with Itk, and Lck, the Src kinase immediately downstream of the TCR. We investigated the expression of Itk, Txk, and Lck in thymocytes and mature lymphocytes following in vitro and in vivo dexamethasone treatment at different time points and doses. Kinase expression was differentially modulated and followed distinct kinetics. Itk was up-regulated in all cell types and conditions tested. Txk was strongly up-regulated in mature lymphocytes but only weakly up-regulated or non-modulated in thymocytes in vitro or in vivo, respectively. Conversely, Lck was down-regulated in thymocytes, but not modulated or up-regulated in mature lymphocytes in the different experimental conditions. This complex behaviour correlates with the presence of both positive and negative glucocorticoid responsive elements (GRE and nGRE, respectively) in the Itk, Txk and Lck genes. To investigate the function associated with Itk up-regulation, dexamethasone-induced apoptosis of thymocytes from Itk-deficient mice was evaluated. Our results demonstrated that Itk deficiency causes increased sensitivity to dexamethasone but not to other pro-apoptotic stimuli. Conclusions Modulation of Itk, Txk, and Lck in thymocytes and mature lymphocytes is another mechanism by which glucocorticoids modulate T-cell activation and differentiation. Itk up-regulation plays a protective role in dexamethasone-treated thymocytes.
    BMC pharmacology & toxicology 07/2014; 15(1):35. DOI:10.1186/2050-6511-15-35
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    • ", 1997 ) . ITK knockout mice were reportedly used in previous stud - ies to investigate the role of ITK in allergic asthma ( Mueller and August , 2003 ) . However , compensatory mechanisms might occur in the embryonic development of the ITK knockout mice . "
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    ABSTRACT: Coxsackievirus B3 (CVB3) infection causes myocarditis, pancreatitis, and aseptic meningitis. Targeting antigen-specific T cell reactions might be a promising way to alleviate the inflammatory response induced by CVB3 infection. IL-2-inducible T-cell kinase (ITK), a member of Tec kinase family expressed mainly in T cells, plays an important role in the activation of T cells. The role of ITK in viral myocarditis induced by CVB3 has not been documented. In this study, we inhibited the ITK expression in Jurkat cells, primary human peripheral blood mononuclear cells (PBMC), and mouse splenocytes by ITK-specific siRNA. The inhibition efficiently suppressed cell proliferation (P<0.05) and T-cell related cytokine secretion (P<0.05). In order to inhibit ITK in vivo, the pGCSIL plasmid containing short hairpin RNAs targeting ITK was constructed and transduced into mice infected with CVB3. ITK-inhibited mice showed reduced cell proliferation (3, 5, and 7 days post-challenge, P<0.05) as well as CD4+ and CD8+ T cells (5 days post-challenge, P<0.05). The altered production of inflammatory cytokines alleviated pathologic heart damage and improved mice survival rate (P<0.05). ITK played an important role in the T cell development and represented a new target for the modulation of T-cell-mediated inflammatory response by CVB3 infection.
    Molecular Immunology 01/2014; 59(1):30-38. DOI:10.1016/j.molimm.2013.12.004 · 2.97 Impact Factor
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