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Cyclosporin A effects during primary and secondary activation of human umbilical cord blood T lymphocytes

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Kadereit_et_al._2001.pdf
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2001

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Kozik, Margaret M.
Junge, Gwendolyn R.
Miller, Robin E.
Slivka, Laura F.
Bos, Linda S.
Daum-Woods, Kathleen
Sramkoski, R. Michael
Jacobberger, James W.
Laughlin, Mary J.

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Experimental Hematology. 2001, 29(7), pp. 903-909. ISSN 0301-472X. Available under: doi: 10.1016/S0301-472X(01)00662-2

Zusammenfassung

Objective: Cyclosporin A (CsA), effective in prophylaxis and treatment of graft-vs-host disease (GVHD) after human allogeneic transplantation, blunts T-cell responses by inhibiting nuclear factor of activated T cells 1 (NFAT1) activation. This laboratory has shown that NFAT1 protein expression is severely reduced in human UCB (umbilical cord blood) T cells. Since UCB is increasingly used as a hematopoietic stem cell source in allogeneic transplantation, it is important to determine whether CsA sensitivity in UCB differs from that of adult T cells.

Methods: Surface flow cytometric analysis, intracellular cytokine staining, flow cytometric analysis of cell death, and thymidine incorporation were used in this study to determine T-cell activation and effector functions during primary and secondary stimulation in the presence of CsA.

Results: Although we observed differential CsA sensitivity of T-cell activation marker (CD69, CD45RO, CD25) upregulation comparing UCB and adult, we did not observe any significant difference in CsA sensitivity of T-cell effector functions. Importantly, we observed reduced IFN-γ and TNF-α expression in UCB T cells both in primary and secondary stimulation, as well as increased rates of activation-induced cell death (AICD).

Conclusion: Thus, our studies do not support the previous hypothesis that reduced GVHD observed after UCB transplantation is attributable to increased CsA sensitivity of UCB T cells. Rather, reduced UCB T-cell cytokine production and increased AICD may be important cellular mechanisms underlying these favorable rates of GVHD in UCB transplant recipients.

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570 Biowissenschaften, Biologie

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ISO 690KADEREIT, Suzanne, Margaret M. KOZIK, Gwendolyn R. JUNGE, Robin E. MILLER, Laura F. SLIVKA, Linda S. BOS, Kathleen DAUM-WOODS, R. Michael SRAMKOSKI, James W. JACOBBERGER, Mary J. LAUGHLIN, 2001. Cyclosporin A effects during primary and secondary activation of human umbilical cord blood T lymphocytes. In: Experimental Hematology. 2001, 29(7), pp. 903-909. ISSN 0301-472X. Available under: doi: 10.1016/S0301-472X(01)00662-2
BibTex
@article{Kadereit2001Cyclo-8168,
  year={2001},
  doi={10.1016/S0301-472X(01)00662-2},
  title={Cyclosporin A effects during primary and secondary activation of human umbilical cord blood T lymphocytes},
  number={7},
  volume={29},
  issn={0301-472X},
  journal={Experimental Hematology},
  pages={903--909},
  author={Kadereit, Suzanne and Kozik, Margaret M. and Junge, Gwendolyn R. and Miller, Robin E. and Slivka, Laura F. and Bos, Linda S. and Daum-Woods, Kathleen and Sramkoski, R. Michael and Jacobberger, James W. and Laughlin, Mary J.}
}
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    <dcterms:abstract xml:lang="eng">Objective: Cyclosporin A (CsA), effective in prophylaxis and treatment of graft-vs-host disease (GVHD) after human allogeneic transplantation, blunts T-cell responses by inhibiting nuclear factor of activated T cells 1 (NFAT1) activation. This laboratory has shown that NFAT1 protein expression is severely reduced in human UCB (umbilical cord blood) T cells. Since UCB is increasingly used as a hematopoietic stem cell source in allogeneic transplantation, it is important to determine whether CsA sensitivity in UCB differs from that of adult T cells.&lt;br /&gt;&lt;br /&gt;Methods: Surface flow cytometric analysis, intracellular cytokine staining, flow cytometric analysis of cell death, and thymidine incorporation were used in this study to determine T-cell activation and effector functions during primary and secondary stimulation in the presence of CsA.&lt;br /&gt;&lt;br /&gt;Results: Although we observed differential CsA sensitivity of T-cell activation marker (CD69, CD45RO, CD25) upregulation comparing UCB and adult, we did not observe any significant difference in CsA sensitivity of T-cell effector functions. Importantly, we observed reduced IFN-γ and TNF-α expression in UCB T cells both in primary and secondary stimulation, as well as increased rates of activation-induced cell death (AICD).&lt;br /&gt;&lt;br /&gt;Conclusion: Thus, our studies do not support the previous hypothesis that reduced GVHD observed after UCB transplantation is attributable to increased CsA sensitivity of UCB T cells. Rather, reduced UCB T-cell cytokine production and increased AICD may be important cellular mechanisms underlying these favorable rates of GVHD in UCB transplant recipients.</dcterms:abstract>
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