Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease

H Zheng, C Matte-Martone, H Li… - Blood, The Journal …, 2008 - ashpublications.org
H Zheng, C Matte-Martone, H Li, BE Anderson, S Venketesan, H Sheng Tan, D Jain, J McNiff
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
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 …
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-α, 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.
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