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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1175-1183. Prepublished online as a Blood First Edition Paper on June 3, 2008; DOI 10.1182/blood-2007-11-125435. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-11-125435v1 112/4/1175    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 Kavanagh, B. Articles by Fong, L. Search for Related Content PubMed PubMed Citation Articles by Kavanagh, B. Articles by Fong, L. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion Brian Kavanagh1,2, Shaun O'Brien1,2, David Lee1,2, Yafei Hou1,2, Vivian Weinberg3, Brian Rini1, James P. Allison4, Eric J. Small1, and Lawrence Fong1,2 1 Division of Hematology/Oncology, 2 Department of Microbiology and Immunology, and 3 Department of Biostatistics, University of California, San Francisco; and 4 Ludwig Center for Cancer Immunotherapy, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY Cytotoxic T lymphocyte–associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4+ T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4+ T cells, but also in the number of CD4+ FoxP3+ Tregs. Although the effects were dose-dependent, CD4+ FoxP3+ regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4+ FoxP3+ regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4+ FoxP3+ Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Verhagen, L. Gabrysova, S. Minaee, C. A. Sabatos, G. Anderson, A. H. Sharpe, and D. C. Wraith Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease PNAS, March 3, 2009; 106(9): 3306 - 3311. [Abstract] [Full Text] [PDF] L. Fong, S. S. Kwek, S. O'Brien, B. Kavanagh, D. G. McNeel, V. Weinberg, A. M. Lin, J. Rosenberg, C. J. Ryan, B. I. Rini, et al. Potentiating Endogenous Antitumor Immunity to Prostate Cancer through Combination Immunotherapy with CTLA4 Blockade and GM-CSF Cancer Res., January 15, 2009; 69(2): 609 - 615. [Abstract] [Full Text] [PDF] J. L. Marshall Time to Shift the Focus of the War: It Is Not All About the Enemy J. Clin. Oncol., January 10, 2009; 27(2): 168 - 169. [Full Text] [PDF] E. M. Schmidt, C. J. Wang, G. A. Ryan, L. E. Clough, O. S. Qureshi, M. Goodall, A. K. Abbas, A. H. Sharpe, D. M. Sansom, and L. S. K. Walker CTLA-4 Controls Regulatory T Cell Peripheral Homeostasis and Is Required for Suppression of Pancreatic Islet Autoimmunity J. Immunol., January 1, 2009; 182(1): 274 - 282. [Abstract] [Full Text] [PDF]

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