Imatinib Mesylate Inhibits Antigen-Specific Memory CD8 T Cell Responses In Vivo

Sinai, Parisa; Berg, Rance E.; Haynie, J. Marshall; Egorin, Merrill J.; Ilaria, Robert; Forman, James

doi:10.4049/jimmunol.178.4.2028

Cited by 31 publications

(23 citation statements)

References 77 publications

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“…Abl kinase activity promotes IL-2 production, which is known to be required for CD127 expression during the late phase of a primary immune response (20)(21)(22)38). Recent studies have demonstrated that inhibitors of Abl kinase, such as Imatinib, inhibit CD127 expression by T cells and memory responses while allowing initial phases of activation, including proliferation, to occur (39). However, in contrast to pan-T cell inhibitors, Sema6D targeting may specifically affect a distinct activated population of T cells.…”

Section: Discussionmentioning

confidence: 99%

Semaphorin 6D regulates the late phase of CD4 ⁺ T cell primary immune responses

O’Connor

Eun

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The semaphorin and plexin family of ligand and receptor proteins provides important axon guidance cues required for development. Recent studies have expanded the role of semaphorins and plexins in the regulation of cardiac, circulatory and immune system function. Within the immune system, semaphorins and plexins regulate cell-cell interactions through a complex network of receptor and ligand pairs. Immune cells at different stages of development often express multiple semaphorins and plexins, leading to multivariate interactions, involving more than one ligand and receptor within each functional group. Because of this complexity, the significance of semaphorin and plexin regulation on individual immune cell types has yet to be fully appreciated. In this work, we examined the regulation of T cells by semaphorin 6D. Both in vitro and in vivo T cell stimulation enhanced semaphorin 6D expression. However, semaphorin 6D was only expressed by a majority of T cells during the late phases of activation. Consequently, the targeted disruption of semaphorin 6D receptor-ligand interactions inhibited T cell proliferation at late but not early phases of activation. This proliferation defect was associated with reduced linker of activated T cells protein phosphorylation, which may reflect semaphorin 6D regulation of c-Abl kinase activity. Semaphorin 6D disruption also inhibited expression of CD127, which is required during the multiphase antigen-presenting cell and T cell interactions leading to selection of long-lived lymphocytes. This work reveals a role for semaphorin 6D as a regulator of the late phase of primary immune responses.immune regulation ͉ lymphocyte selection ͉ response maturation

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Section: Discussionmentioning

confidence: 99%

Semaphorin 6D regulates the late phase of CD4 ⁺ T cell primary immune responses

O’Connor

Eun

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…In vitro studies show inhibition of the development of CD34 + progenitor cell-derived dendritic cells with a reduced capacity to induce a cytotoxic T-cell response [10] and a dose-dependent reduction of the T-cell population [11][12][13]. In vivo studies demonstrate reversible and dosedependent lymphopenia and hypogammaglobulinemia [14], and impaired CD8 T-cell responses [15,16]. Interestingly, MUMPRECHT et al [16] observed an intact control of primary viral infections in spite of the impaired cytotoxic T-cell response.…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia

Daniëls¹,

Vonk‐Noordegraaf²,

Janssen³

et al. 2009

European Respiratory Journal

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Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB.There are several reports suggesting that imatinib might impair the immune system, leading to a variety of infections, including varicella zoster and hepatitis B. Control of TB in healthy individuals is achieved through acquired immunity, in which antigen-specific T-cells and macrophages arrest growth of Mycobacterium tuberculosis bacilli and maintain control over persistent bacilli. In the chronic stage of the infection, CD8+ T-cells assist macrophages in controlling intracellular mycobacteria. The T-cell receptor orchestrates this process.The fact that tyrosine kinases play an important role in T-cell receptor signal transduction and that imatinib has been shown to affect T-cell receptor signal transduction, presents a mechanism by which imatinib might impair control of Mycobacterium tuberculosis; thereby leaving the host susceptible to reactivation of tuberculosis.

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“…NaBve T cells are more sensitive than memory T cells to the inhibitory effects of dasatinib. Murine cytotoxic memory T cells are more sensitive than naBve CD8 + T cells to the inhibitory effects of imatinib (26,27 …”

Section: Differential Sensitivity Of Helper and Cytotoxic T Cells To mentioning

confidence: 99%

Profound Inhibition of Antigen-Specific T-Cell Effector Functions by Dasatinib

Weichsel

Dix²,

Wooldridge

et al. 2008

Clinical Cancer Research

127

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Purpose: The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for the treatment of chronic myeloid leukemia and Ph + acute lymphoblastic leukemia. Because SRC kinases are known to play an important role in physiologicT-cell activation, we analyzed the immunobiological effects of dasatinib on T-cell function. The effect of dasatinib on multiple T-cell effector functions was examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine kinase inhibitor staurosporine was used as a comparator. Experimental Design: Purified human CD3 + cells and virus-specific CD8 + Tcells from healthy blood donors were studied directly ex vivo ; antigen-specific effects were confirmed in defined T-cell clones. Functional outcomes included cytokine production (interleukin-2, IFNg, and tumor necrosis factor a), degranulation (CD107a/b mobilization), activation (CD69 up-regulation), proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), apoptosis/necrosis induction, and signal transduction. Results: Both dasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and degranulation in a dose-dependent manner. Mechanistically, this was mediated by the blockade of early signal transduction events and was not due to loss of T-cell viability. Overall, CD4 + T cells seemed to be more sensitive to these effects than CD8 + Tcells, and naBve Tcells more sensitive than memoryT-cell subsets. The inhibitory effects of dasatinib were so profound that all T-cell effector functions were shut down at therapeutically relevant concentrations. Conclusion: These findings indicate that caution is warranted with use of this drug in the clinical setting and provide a rationale to explore the potential of dasatinib as an immunosuppressant in the fields of transplantation and T-cell^driven autoimmune diseases.

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Imatinib Mesylate Inhibits Antigen-Specific Memory CD8 T Cell Responses In Vivo

Cited by 31 publications

References 77 publications

Semaphorin 6D regulates the late phase of CD4 ⁺ T cell primary immune responses

Semaphorin 6D regulates the late phase of CD4 ⁺ T cell primary immune responses

Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia

Profound Inhibition of Antigen-Specific T-Cell Effector Functions by Dasatinib

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Imatinib Mesylate Inhibits Antigen-Specific Memory CD8 T Cell Responses In Vivo

Cited by 31 publications

References 77 publications

Semaphorin 6D regulates the late phase of CD4 + T cell primary immune responses

Semaphorin 6D regulates the late phase of CD4 + T cell primary immune responses

Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia

Profound Inhibition of Antigen-Specific T-Cell Effector Functions by Dasatinib

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Product

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Semaphorin 6D regulates the late phase of CD4 ⁺ T cell primary immune responses

Semaphorin 6D regulates the late phase of CD4 ⁺ T cell primary immune responses