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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4070-4077. Prepublished online as a Blood First Edition Paper on February 12, 2004; DOI 10.1182/blood-2003-08-2934. This Article Full Text (PDF) All Versions of this Article: 2003-08-2934v1 103/11/4070    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuramoto, K. Articles by Dunbar, C. E Search for Related Content PubMed PubMed Citation Articles by Kuramoto, K. Articles by Dunbar, C. E Social Bookmarking                   What's this? Submitted August 28, 2003 Accepted January 10, 2004 The Impact of Chronic Cytokine Therapy on Clonal Dynamics in Non-Human Primates Ken Kuramoto, Dean A Follmann, Peiman Hematti, Stephanie Sellers, Brian A Agricola, Mark E Metzger, Robert E Donahue, Christof von Kalle, and Cynthia E Dunbar* Hematology Branch, NHLBI, NIH, Bethesda, MD, USA Biostatistics Research Branch, NIAID, NIH, Bethesda, MD, USA Children's Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA * Corresponding author; email: dunbarc{at}mail.nih.gov. Hematopoietic cytokines such as filigrastim are used extensively to stimulate granulocyte production or to mobilize hematopoietic progenitors into the circulation, however their impact on more primitive hematopoietic progenitor and stem cells in vivo is unknown, particularly in large animals or humans. In particular, there is concern that chronic therapy with cytokines could result in stem cell exhaustion or clonal dominance, however, direct assessment of the dynamics of individual stem and progenitor cell clones in vivo has not been previously reported. A number of models can be proposed regarding the mechanisms by which the marrow responds to cytokine stimulation, including recruitment of previously quiescent clones, stimulation of proliferation of already active clones, or prevention of apoptosis of more mature progenitors from all clones. Using retroviral marking and comprehensive insertion site tracking of individual stem and progenitor cell clones in two rhesus macaques, we analyzed the impact of chronic administration of G-CSF, or a combination of G-CSF plus stem cell factor (SCF). The overall number of contributing clones remained constant, and the relative output form each clone did not change significantly during or following cytokine treatments. These results suggest that individual transduced stem or progenitor cells can contribute to hematopoiesis for prolonged periods, with no evidence for an impact of G-CSF or G-CSF/SCF on the number, the lifespan or the relative activity of individual stem or progenitor cell clones. These relevant large animal studies are reassuring regarding clinical applications of cytokines, and provide new insights into their mechanisms of action. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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