title: Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia.
abstract: Adoptive immunotherapy with donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) may not only mediate Graft-versus-Leukemia (GvL) reactivity, but also induce Graft-versus-Host Disease (GvHD). As HLA-class II molecules are predominantly expressed on hematopoietic cells, CD4+ T cells may selectively mediate GvL reactivity without GvHD. Here, we assessed the capacity of human CD4+ T cells to act as sole mediators of GvL reactivity in a NOD/scid mouse model for human acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crisis. Highly purified CD4+ DLI eradicated the leukemic cells. The anti-tumor immunity was mediated by a polyclonal CD4+ T cell response comprising cytokine-producing T-helper and cytolytic T-effector cells directed against the mismatched HLA-class II molecules of the patients. Furthermore, primary leukemic cells acquired an antigen-presenting cell (APC) phenotype in vivo after DLI, as well as in vitro after co-culture with leukemia-specific CD4+ T cells. In conclusion, our results show that CD4+ T cells can be strong mediators of anti-tumor immunity, and provide evidence that cross-talk between CD4+ T cells and leukemic cells is the basis for induction of leukemic cells with an APC phenotype. These data emphasize the clinical relevance of CD4+ T cell based immunotherapy as treatment modality for hematological malignancies after alloSCT.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. s.stevanovic@lumc.nl
authors.forename: S
authors.initials: S
authors.lastname: Stevanović
authors.forename: M
authors.initials: M
authors.lastname: Griffioen
authors.forename: B A
authors.initials: BA
authors.lastname: Nijmeijer
authors.forename: M L J
authors.initials: ML
authors.lastname: van Schie
authors.forename: A N
authors.initials: AN
authors.lastname: Stumpf
authors.forename: C E
authors.initials: CE
authors.lastname: Rutten
authors.forename: R
authors.initials: R
authors.lastname: Willemze
authors.forename: J H F
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology