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Blood, 29 October 2009, Vol. 114, No. 18, pp. 3831-3840. Prepublished online as a Blood First Edition Paper on August 24, 2009; DOI 10.1182/blood-2009-03-212134. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-03-212134v1 114/18/3831    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 CrossRef Google Scholar Articles by Cui, Y. Articles by Mackall, C. L. PubMed PubMed Citation Articles by Cui, Y. Articles by Mackall, C. L. Related Collections Immunobiology Transplantation Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts Yongzhi Cui1, Hua Zhang1, Joanna Meadors1, Rita Poon1, Martin Guimond1, and Crystal L. Mackall1 1 Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD Lymphopenia enhances the effectiveness of adoptive immunotherapy by facilitating expansion of transferred T cells but also limits the T-cell repertoire available to mediate immune responses and, in humans, is associated with chronic immune dysfunction. Previous studies concluded that lymphopenia augments adoptive immunotherapy by diminishing Tregs and increasing homeostatic cytokines. We sought to determine whether targeted therapies that replicate the physiology of lymphopenia in lymphoreplete hosts could provide a similarly supportive milieu. Pmel-1 T cells were transferred to B16-bearing lymphopenic versus lymphoreplete mice receiving CD25 and/or recombinant human interleukin-7. Although CD25-based Treg depletion was inefficient because of peripheral expansion of CD4+CD25–FOXP3+ cells, outcomes were better in CD25-treated lymphoreplete hosts than in lymphopenic hosts, and adoptive immunotherapy was most effective in lymphoreplete hosts receiving CD25 plus recombinant human interleukin-7. Lymphopenic hosts supported increased proliferation of adoptively transferred antigen-specific T cells, but cells transferred to lymphoreplete recipients receiving targeted therapies showed superior function. Further, determinant spreading was substantial in lymphoreplete hosts but absent in lymphopenic hosts. These results demonstrate that targeted therapies delivered to mimic the "physiology of lymphopenia" enhance the efficacy of adoptive immunotherapy in lymphoreplete hosts and provide a potentially superior alternative to the induction of lymphopenia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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