Journal
BLOOD
Volume 111, Issue 4, Pages 2476-2484Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-08-109678
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Funding
- NCI NIH HHS [R01-CA96943, R01 CA096943] Funding Source: Medline
- NHLBI NIH HHS [R01-HL66279, T32 HL007974, T32 HL007262, R01 HL066279, T32 HL07262-31] Funding Source: Medline
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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 (T-EMs) do not cause GVHD but transfer functional T-cell memory. In the present work, we demonstrate in an MHC-mismatched model that CD4(+) T-EMs (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 T-EM-mediated GVL, but that GVL is retained when killing via FasL, TNF-alpha, TRAIL, and perforin is individually impaired. However, T-EM-mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken together, our studies identify T-EMs 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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