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  • 1
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    γδ T cells affect IL-4 production and B-cell tolerance
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 1 ( 2015-01-06)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 1 ( 2015-01-06)
    Abstract: γδ T cells can influence specific antibody responses. Here, we report that mice deficient in individual γδ T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of αβ T cells. One strain with a partial γδ deficiency that increases IgE antibodies also displayed increases in IL-4–producing T cells (both residual γδ T cells and αβ T cells) and in systemic IL-4 levels. Its B cells expressed IL-4–regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4–inducible IL-4 receptor α and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice. Our data suggest that γδ T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1415107111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
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  • 2
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    Antigen-Specific Suppression of Humoral Immunity by Anergic Ars/A1 B Cells
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 189, No. 9 ( 2012-11-01), p. 4275-4283
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 189, No. 9 ( 2012-11-01), p. 4275-4283
    Abstract: Autoreactive anergic B lymphocytes are considered to be dangerous because of their potential for activation and recruitment into autoimmune responses. However, they persist for days and constitute ∼5% of the B cell pool. We assessed their functional potential in the Ars/A1 transgene model, where anergic B cells express a dual-reactive Ag receptor that binds, in addition to a self-Ag, the hapten p-azophenylarsonate (Ars). When Ars/A1 B cells were transferred into adoptive recipients that were immunized with foreign proteins covalently conjugated with Ars, endogenous IgG immune responses to both were selectively and severely diminished, and the development of T helper cells was impaired. Approximately 95% inhibition of the anti-Ars response was attained with ∼4000 transferred Ars/A1 B cells through redundant mechanisms, one of which depended on their expression of MHC class II but not upon secretion of IL-10 or IgM. This Ag-specific suppressive activity implicates the autoreactive anergic B cell as an enforcer of immunological tolerance to self-Ags.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1201818
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
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  • 3
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    γδ T Cells Shape Preimmune Peripheral B Cell Populations
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1 ( 2016-01-01), p. 217-231
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1 ( 2016-01-01), p. 217-231
    Abstract: We previously reported that selective ablation of certain γδ T cell subsets, rather than removal of all γδ T cells, strongly affects serum Ab levels in nonimmunized mice. This type of manipulation also changed T cells, including residual γδ T cells, revealing some interdependence of γδ T cell populations. For example, in mice lacking Vγ4+ and Vγ6+ γδ T cells (B6.TCR-Vγ4−/−/6−/−), we observed expanded Vγ1+ cells, which changed in composition and activation and produced more IL-4 upon stimulation in vitro, increased IL-4 production by αβ T cells as well as spontaneous germinal center formation in the spleen, and elevated serum Ig and autoantibodies. We therefore examined B cell populations in this and other γδ-deficient mouse strains. Whereas immature bone marrow B cells remained largely unchanged, peripheral B cells underwent several changes. Specifically, transitional and mature B cells in the spleen of B6.TCR-Vγ4−/−/6−/− mice and other peripheral B cell populations were diminished, most of all splenic marginal zone (MZ) B cells. However, relative frequencies and absolute numbers of Ab-producing cells, as well as serum levels of Abs, IL-4, and BAFF, were increased. Cell transfers confirmed that these changes are directly dependent on the altered γδ T cells in this strain and on their enhanced potential of producing IL-4. Further evidence suggests the possibility of direct interactions between γδ T cells and B cells in the splenic MZ. Taken together, these data demonstrate the capability of γδ T cells of modulating size and productivity of preimmune peripheral B cell populations.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1501064
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
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  • 4
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    Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics ( 2023-09-30)
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), ( 2023-09-30)
    Abstract: Brentuximab vedotin, a CD30-directed antibody–drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic disruption of the microtubule network eliciting a robust endoplasmic reticulum (ER) stress response that culminates in the induction of the classic hallmarks of immunogenic cell death (ICD). In accordance with the induction of ICD, brentuximab vedotin-killed lymphoma cells drove innate immune cell activation in vitro and in vivo. In the “gold standard” test of ICD, vaccination of mice with brentuximab vedotin or free MMAE-killed tumor cells protected animals from tumor rechallenge; in addition, T cells transferred from previously vaccinated animals slowed tumor growth in immunodeficient mice. Immunity acquired from killed tumor cell vaccination was further amplified by the addition of PD-1 blockade. In a humanized model of CD30+ B cell tumors, treatment with brentuximab vedotin drove the expansion and recruitment of autologous EBV-reactive CD8+ T cells potentiating the activity of anti–PD-1 therapy. Together these data support the ability of brentuximab vedotin and MMAE to drive ICD in tumor cells resulting in the activation of antigen-presenting cells and augmented T-cell immunity. These data provide a strong rationale for the clinical combination of brentuximab vedotin and other MMAE-based ADCs with checkpoint inhibitors.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-23-0118
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract 1789: CD30+T regulatory cells, but not CD30+CD8 T cells, are impaired following brentuximab vedotin treatment in vitro and in vivo
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1789-1789
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1789-1789
    Abstract: Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) directed against CD30, a TNF receptor superfamily (TNFRSF) member highly expressed on Reed Sternberg cells in Hodgkin lymphoma (HL) and also commonly expressed in a number of other lymphoid malignancies such as ALCL and CTCL. BV consists of a monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. MMAE-based ADC antitumor activity primarily results from intracellular payload release, leading to mitotic arrest and apoptotic cell death, although secondary MOAs may exist. CD30 is mostly absent on resting peripheral lymphocytes, but is known to be transiently upregulated on both CD4+ and CD8+ T cells following activation. Recently, CD30 was identified, by separate research groups, as a marker differentially upregulated by human intratumoral T regulatory cells (Tregs). This recent observation raises the possibility that BV could target and eliminate intratumoral CD30+ Tregs. Abundant evidence shows that tumor-specific CD8+ T cells are paramount to antitumor immunity. In contrast, tumor-resident T regulatory cells have been shown to counteract immunosurveillance and promote tumor escape. Given that CD30 may be expressed on both activated CD8+ T cells and intratumoral Tregs, we explored the outcome of BV treatment on each cell type. In this work, we show that BV directly depleted inducible and primary CD30+ Tregs in vitro, in a dose-dependent manner, while CD30+ CD8+ T cells were unaffected. Moreover, BV selectively depleted Tregs in a Treg:CD8 T cell co-culture suppression assay, resulting in expansion of proliferating CD8+ T cells. In vivo, using a humanized mouse model of graft-versus-host disease (xeno-GVHD), treatment of mice with BV significantly reduced splenic Treg numbers, while amplifying total xeno-reactive CD8+ cytotoxic T cells. In an effort to understand BV's selective impairment of Tregs, we evaluated CD30 expression following in vitro activation with CD3/CD28. Freshly isolated Tregs showed notably accelerated CD30 expression kinetics along with significantly higher peak receptor number compared to CD8+ T cells. Furthermore, assays confirmed that the heightened receptor expression on Tregs translated into increased BV internalization and drug-linker cleavage. Finally, CD8+ T cells were much more efficient at effluxing rhodamine than Tregs, suggesting lowered drug accumulation and exposure over time. Together, these data raise the novel possibility that brentuximab vedotin may be able to positively impact the Treg:CD8 T cell balance in the tumor microenvironment through selective depletion of CD30+ Tregs, but not activated CD8+ T cells. Citation Format: Ryan A. Heiser, Bryan M. Grogan, Luke S. Manlove, Shyra J. Gardai. CD30+T regulatory cells, but not CD30+CD8 T cells, are impaired following brentuximab vedotin treatment in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1789.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1789
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Abstract 5588: Brentuximab vedotin-driven immunogenic cell death enhances antitumor immune responses, and is potentiated by PD1 inhibition in vivo
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5588-5588
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5588-5588
    Abstract: Brentuximab vedotin (BV) is an antibody-drug conjugate directed against CD30 consisting of a monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. BV antitumor activity is thought to be primarily the result of intracellular payload release leading to mitotic arrest and apoptotic cell death. We have demonstrated that BV drives apoptosis in a manner consistent with immunogenic cell death (ICD) including activation of the unfolded protein/ER stress response with a concomitant increase in surface expression of calreticulin and HSP70. In this study, we provide evidence that in vivo administration of BV leads to directed proinflammatory immune responses against the tumor and this activity is further potentiated by anti-PD-1 therapy. To examine the immunomodulatory effects of BV-induced ICD in vivo, we employed 3 murine model systems. In the first model, BV treatment induced ICD in subcutaneously-engrafted CD30+ L540cy cells, generated strong chemotactic responses detectable within the tumor and in circulation, and increased infiltration of dendritic cells into the tumor microenvironment. To assess whether BV-driven ICD could confer specific antitumor immunity, we used a model in which ICD was induced in BV-treated human CD30-expressing A20 lymphoma cells in vitro. These cells were used to immunize wild-type BALB/c mice followed by live A20 challenge. Immunization with BV-treated cells, undergoing ICD, delayed tumor growth and improved survival compared to mice immunized with flash-frozen cells. Furthermore, administering anti-PD-1 to mice immunized with BV-treated cells displayed marked combinatorial effects, leading to improved tumor clearance compared to either treatment alone. Additionally, T cells isolated from mice immunized with BV-treated cells and transferred into tumor-bearing immunodeficient mice resulted in tumor regression and survival, demonstrating robust T cell memory. Lastly, we employed a humanized tumor model pairing CD30+ PDL1+ PDL2+ lymphoblastoid cell line (LCL) xenografts with adoptively transferred autologous PBMC. In this setting, mice treated with suboptimal doses of BV showed greatly enhanced cytotoxic T cell and NK cell accumulation in LCL tumors resulting in accelerated immune-mediated tumor clearance. Tumor regression was further accelerated by treating mice with a combination of BV and a human PD1 inhibitor, demonstrating complementary modes of action for these agents. Together, these data indicate that targeted treatment with the MMAE antibody drug conjugate brentuximab vedotin drives an immunogenic form of tumor cell death that enhances innate and adaptive antitumor immunity. Combination of BV with PD1 inhibitors resulted in greater antitumor activity than either agent alone. Multiple clinical trials are ongoing to evaluate the efficacy of this treatment pairing. Citation Format: Anthony T. Cao, Che-Leung Law, Shyra J. Gardai, Ryan A. Heiser. Brentuximab vedotin-driven immunogenic cell death enhances antitumor immune responses, and is potentiated by PD1 inhibition in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5588. doi:10.1158/1538-7445.AM2017-5588
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5588
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 7
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    Abstract 5551: SGN-2FF: A small-molecule inhibitor of fucosylation modulates immune cell activity in preclinical models and demonstrates pharmacodynamic activity in early phase 1 analysis
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5551-5551
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5551-5551
    Abstract: SGN-2FF, an orally bioavailable small molecule inhibitor of glycoprotein fucosylation, demonstrates encouraging preclinical antitumor activity in mouse models with suggested multiple mechanisms of action, including direct and indirect effects on immune cells, tumor cells, and the tumor microenvironment. The effects of SGN-2FF were evaluated on tumors implanted in multiple strains of mice to determine how differences in the immune repertoire affect the antitumor activity. SGN-2FF treatment of nude mice, which maintain functional B cells and antibody production, resulted in a delay in LS174T tumor growth compared with untreated mice, while LS174T tumors in SCID mice, which lack B cells, were unaffected by SGN-2FF. These data suggest that activity of SGN-2FF in nude mice may be dependent on residual B cells and circulating antibodies. The antitumor effect of SGN-2FF in syngeneic mouse models with intact immune systems also appears to be dependent on T cell activity. Transfer of T cells isolated from SGN-2FF-treated tumor-bearing mice to naïve tumor-bearing mice was sufficient to delay tumor growth. T cells isolated from untreated tumor-bearing mice did not have the same effect. These results demonstrate that afucosylated immune cells play a key role in the preclinical activity of SGN-2FF. Various preclinical assays were used to detect SGN-2FF-mediated changes in cellular and IgG fucosylation important for biological activity. These assays are being applied in evaluating patient samples in the ongoing phase 1, multicenter, dose-escalation study investigating the safety, tolerability, PK, and biomarkers of antitumor activity of SGN-2FF administered orally to adult patients with advanced solid tumors (NCT# 02952989). Changes in peripheral IgG fucosylation, absolute neutrophil count, and immune cell surface fucosylation were identified as initial biomarkers for proof of pharmacodynamic activity. Preliminary data following daily doses of SGN-2FF demonstrate that cell surface fucosylation on granulocytes was significantly reduced and neutrophil count was significantly increased in 6 of 7 treated subjects; additionally, IgG fucosylation was significantly decreased in 7 of 7 subjects. PK have been characterized, and preliminary results are within the expected range as predicted from preclinical studies. Following daily administration of SGN-2FF, accumulation of the active metabolite, GDP-2FF, was observed intracellularly, while no accumulation of SGN-2FF was observed in plasma. Collectively, these data demonstrate robust biological effects of SGN-2FF. The pharmacodynamic biomarkers and PK analysis are informing next steps in identifying an optimal dose and dosing schedule for SGN-2FF. Citation Format: Nicole M. Okeley, Ryan A. Heiser, Weiping Zeng, Shawna Mae Hengel, Jason Wall, Peter C. Haughney, Timothy Anthony Yap, Francisco Robert, Rachel E. Sanborn, Howard Burris, Laura Q. Chow, Khanh T. Do, Martin Gutierrez, Karen Reckamp, Amy Weise, D Ross Camidge, John Strickler, Conor Steuer, Zejing Wang, Megan M. O'Meara, Stephen C. Alley, Shyra J. Gardai. SGN-2FF: A small-molecule inhibitor of fucosylation modulates immune cell activity in preclinical models and demonstrates pharmacodynamic activity in early phase 1 analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5551.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5551
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 8
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    Aborted Germinal Center Reactions and B Cell Memory by Follicular T Cells Specific for a B Cell Receptor V Region Peptide
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 187, No. 1 ( 2011-07-01), p. 212-221
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 187, No. 1 ( 2011-07-01), p. 212-221
    Abstract: A fundamental problem in immunoregulation is how CD4+ T cells react to immunogenic peptides derived from the V region of the BCR that are created by somatic mechanisms, presented in MHC II, and amplified to abundance by B cell clonal expansion during immunity. BCR neo Ags open a potentially dangerous avenue of T cell help in violation of the principle of linked Ag recognition. To analyze this issue, we developed a murine adoptive transfer model using paired donor B cells and CD4 T cells specific for a BCR-derived peptide. BCR peptide-specific T cells aborted ongoing germinal center reactions and impeded the secondary immune response. Instead, they induced the B cells to differentiate into short-lived extrafollicular plasmablasts that secreted modest quantities of Ig. These results uncover an immunoregulatory process that restricts the memory pathway to B cells that communicate with CD4 T cells via exogenous foreign Ag.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1002328
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
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  • 9
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    Activation and Tolerance in CD4+ T Cells Reactive to an Immunoglobulin Variable Region
    Rockefeller University Press ; 2004
    In:  The Journal of Experimental Medicine Vol. 200, No. 1 ( 2004-07-05), p. 1-11
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 200, No. 1 ( 2004-07-05), p. 1-11
    Abstract: Antibody diversity creates an immunoregulatory challenge for T cells that must cooperate with B cells, yet discriminate between self and nonself. To examine the consequences of T cell reactions to the B cell receptor (BCR), we generated a transgenic (Tg) line of mice expressing a T cell receptor (TCR) specific for a κ variable region peptide in monoclonal antibody (mAb) 36-71. The κ epitope was originally generated by a pair of somatic mutations that arose naturally during an immune response. By crossing this TCR Tg mouse with mice expressing the κ chain of mAb 36-71, we found that κ-specific T cells were centrally deleted in thymi of progeny that inherited the κTg. Maternally derived κTg antibody also induced central deletion. In marked contrast, adoptive transfer of TCR Tg T cells into κTg recipients resulted in T and B cell activation, lymphadenopathy, splenomegaly, and the production of IgG antichromatin antibodies by day 14. In most recipients, autoantibody levels increased with time, Tg T cells persisted for months, and a state of lupus nephritis developed. Despite this, Tg T cells appeared to be tolerant as assessed by severely diminished proliferative responses to the Vκ peptide. These results reveal the importance of attaining central and peripheral T cell tolerance to BCR V regions. They suggest that nondeletional forms of T tolerance in BCR-reactive T cells may be insufficient to preclude helper activity for chromatin-reactive B cells.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20031234
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2004
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  • 10
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    Developmental, Molecular, and Genetic Dissection of I Na In Vivo in Embryonic Zebrafish Sensory Neurons
    American Physiological Society ; 2005
    In:  Journal of Neurophysiology Vol. 93, No. 6 ( 2005-06), p. 3582-3593
    Details
    In: Journal of Neurophysiology, American Physiological Society, Vol. 93, No. 6 ( 2005-06), p. 3582-3593
    Abstract: The presence of multiple Na v 1 isotypes within a neuron and the lack of specific blockers hamper identification of the in vivo roles of sodium current ( I Na ) components, especially during embryonic stages. To identify the functional properties of I Na components in vivo in developing neurons, we took a molecular genetic approach. Embryonic zebrafish Rohon–Beard (RB) mechanosensory neurons express two different sodium channel isotypes: Na v 1.1 and Na v 1.6. To examine the properties of Na v 1.1- and Na v 1.6-encoded currents in RB cells at different developmental stages, we eliminated the contribution of Na v 1.6 and Na v 1.1 channels, respectively, using an antisense morpholino (MO) approach. MOs were injected into one-cell stage embryos, and RB sodium currents were recorded using patch-clamp techniques in both conventional whole cell mode as well from nucleated patches. Only a subset of RB cells appeared to be affected by the Na v 1.1MO. Overall, the effect of the Na v 1.1MO was a small 25% average reduction in current amplitude. Further, Na v 1.1MO effects were most pronounced in RB cells of younger embryos. In contrast, the effects of the Na v 1.6 MO were observed in all cells and increased as development proceeded. These results indicated that developmental upregulation of RB I Na entailed an increase in the number of functional Na v 1.6 channels. In addition, analysis of voltage-dependent steady-state activation and inactivation parameters revealed that specific functional properties of channels were also developmentally regulated. Finally, analysis of macho mutants indicated that developmental upregulation of I Na was absent in RB cells. These results indicate that MOs are a useful tool for the molecular dissection and analysis of ion channel function in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-3077 , 1522-1598
    URL: Article
    DOI: 10.1152/jn.01070.2004
    RVK:
    XA 10000 ; XA 552555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2005
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