title: Donor T cells administered over HLA class II barriers mediate antitumor immunity without broad off-target toxicity in a NOD/scid mouse model of acute leukemia.
abstract: Alloreactive (allo)-HLA-directed T cell responses after HLA-mismatched allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion are typically considered detrimental responses mediating graft-versus-host disease (GVHD). Allo-HLA-reactive T cells with beneficial and selective graft-versus-leukemia (GVL) reactivity, however, can also be identified within an HLA-mismatched context. We investigated whether allo-HLA class II-directed T cells with beneficial GVL reactivity induced in NOD/scid mice engrafted with human chronic myelogenous leukemia in lymphoid blast crisis after treatment with donor lymphocyte infusion - mediated detrimental xenogeneic GVHD as a result of broad off-target cross-reactivity. The results demonstrate that beneficial GVL reactivity and xenogeneic GVHD are mediated by separate T cells. GVL reactivity was mediated by human T cells recognizing allo-HLA class II molecules, whereas xenoreactivity was exerted by human T cells recognizing H-2 molecules. Taken together, our data indicate a limited risk for detrimental off-target effects by allo-HLA class II-directed T cells and thereby provide a basis for the development of strategies for selecting allo-HLA-restricted T cells with selective GVL reactivity for adoptive transfer after HLA-mismatched allogeneic hematopoietic stem cell transplantation.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. s.stevanovic@lumc.nl
authors.forename: Sanja
authors.initials: S
authors.lastname: Stevanović
authors.forename: Bart A
authors.initials: BA
authors.lastname: Nijmeijer
authors.forename: Marianke L J
authors.initials: ML
authors.lastname: van Schie
authors.forename: Daniela C F
authors.initials: DC
authors.lastname: Salvatori
authors.forename: Saskia
authors.initials: S
authors.lastname: Maas
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D016219:Immunotherapy, Adoptive; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014184:Transplantation, Homologous
chemical_list: D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II