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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5399-5406. Prepublished online as a Blood First Edition Paper on March 7, 2007; DOI 10.1182/blood-2006-12-062943. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-12-062943v1 109/12/5399    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Snyder, J. T. Articles by Ragheb, J. A. Search for Related Content PubMed PubMed Citation Articles by Snyder, J. T. Articles by Ragheb, J. A. Related Collections Immunobiology Cell Cycle Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Direct inhibition of CD40L expression can contribute to the clinical efficacy of daclizumab independently of its effects on cell division and Th1/Th2 cytokine production James T. Snyder1, Jijia Shen1, Hooman Azmi1, Jeannie Hou2, Daniel H. Fowler2, and Jack A. Ragheb1 1 Laboratory of Immunology, National Eye Institute and 2 Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD Humanized anti-CD25 antibodies (eg, daclizumab) have been successfully used to treat several autoimmune diseases. Paradoxically, IL-2 blockade in mice can induce autoimmunity. An interspecies difference in the relative contribution of IL-2 to CD25+ T regulatory cell (CD25+Treg) versus CD25+ effector cell function might explain this conundrum. Consistent with this are reports that daclizumab inhibits human CD25+ effector cell cytokine production by blocking the expression of CD40L. However, in mice, IL-4 and IL-12 regulate CD40L expression. As human Th1/Th2 cytokine production is also dependent on IL-2, daclizumab's inhibition of CD40L expression could be due to an indirect, rather than a direct, effect of IL-2. Here, we clarify the mechanisms underlying CD40L expression. In contrast to the mouse, human CD40L is regulated by CD28 signaling and IL-2, not the principal Th1/Th2-polarizing cytokines. We find that CD40L is expressed on naive and memory cells and inhibited by daclizumab independently of cell division. Collectively, our results indicate that daclizumab could inhibit CD25+ effector T-cell function in vivo by directly blocking CD40L expression. This difference between mice and human may help explain the paradoxical effects of IL-2R blockade in the 2 species. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Halwani, J. D. Boyer, B. Yassine-Diab, E. K. Haddad, T. M. Robinson, S. Kumar, R. Parkinson, L. Wu, M. K. Sidhu, R. Phillipson-Weiner, et al. Therapeutic Vaccination with Simian Immunodeficiency Virus (SIV)-DNA+IL-12 or IL-15 Induces Distinct CD8 Memory Subsets in SIV-Infected Macaques J. Immunol., June 15, 2008; 180(12): 7969 - 7979. [Abstract] [Full Text] [PDF] J. W. Rose, J. B. Burns, J. Bjorklund, J. Klein, H. E. Watt, and N. G. Carlson Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results Neurology, August 21, 2007; 69(8): 785 - 789. [Abstract] [Full Text] [PDF]

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