Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease.
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.
Penn State Milton S. Hershey Medical Center, Department of Medicine, Hershey, PA, USA.
Hong
H
Zheng
Catherine
C
Matte-Martone
Hongmei
H
Li
Britt E
BE
Anderson
Srividhya
S
Venketesan
Hung
H
Sheng Tan
Dhanpat
D
Jain
Jennifer
J
McNiff
Warren D
WD
Shlomchik
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D007156:Immunologic Memory; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy*; D017710:Lymphocyte Transfusion; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D014184:Transplantation, Homologous / Q000276:immunology