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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2476-2484. Prepublished online as a Blood First Edition Paper on November 28, 2007; DOI 10.1182/blood-2007-08-109678. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-08-109678v1 111/4/2476    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 Zheng, H. Articles by Shlomchik, W. D. PubMed PubMed Citation Articles by Zheng, H. Articles by Shlomchik, W. D. Related Collections Transplantation Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease Hong Zheng1, Catherine Matte-Martone2, Hongmei Li2, Britt E. Anderson3, Srividhya Venketesan2, Hung Sheng Tan2, Dhanpat Jain4, Jennifer McNiff5, and Warren D. Shlomchik2 1 Penn State Milton S. Hershey Medical Center, Department of Medicine, Hershey, PA; 2 Section of Medical Oncology and Department of Immunobiology; 3 Department of Laboratory Medicine, 4 Department of Pathology, and 5 Department of Dermatology, Yale University School of Medicine, New Haven, CT Much of the efficacy of allogeneic hematopoietic stem cell transplantation (alloSCT) in curing hematologic malignancies is due to a graft-versus-leukemia (GVL) effect mediated by donor T cells that recognize recipient alloantigens on leukemic cells. Donor T cells are also important for reconstituting immunity in the recipient. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-versus-host disease (GVHD). We previously reported that donor CD4+ effector memory T cells (TEMs) do not cause GVHD but transfer functional T-cell memory. In the present work, we demonstrate in an MHC-mismatched model that CD4+ TEMs (unprimed to recipient antigens) mediate GVL against clinically relevant mouse models of chronic phase and blast crisis chronic myelogenous leukemia, without causing GVHD. By creating gene-deficient leukemias and using perforin-deficient T cells, we demonstrate that direct cytolytic function is essential for TEM-mediated GVL, but that GVL is retained when killing via FasL, TNF-, TRAIL, and perforin is individually impaired. However, TEM-mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken together, our studies identify TEMs as a clinically applicable cell therapy for promoting GVL and immune reconstitution, particularly in MHC-mismatched haploidentical alloSCTs in which T cell–depleted allografts are commonly used to minimize GVHD. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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