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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.
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Submitted August 28, 2007
Accepted November 24, 2007
Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease
Hong Zheng, Catherine Matte-Martone, Hongmei Li, Britt E Anderson, Srividhya Venketesan, Hung Sheng Tan, Dhanpat Jain, Jennifer McNiff, and Warren D. Shlomchik*
Internal Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
Section of Medical Oncology and Department of Immunology, Yale University School of Medicine, New Haven, CT, United States
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States
Department of Pathology, Yale University School of Medicine, New Haven, CT, United States
Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States
* Corresponding author; email: warren.shlomchik{at}yale.edu.
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 (TEM) do not cause GVHD but transfer functional T cell memory. In the present work we demonstrate in an MHC-mismatched model that CD4+ TEM (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 are individually impaired. However, TEM mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken together, our studies identify TEM 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.
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