title: In vitro induction of myeloid leukemia-specific CD4 and CD8 T cells by CD40 ligand-activated B cells gene modified to express primary granule proteins.
abstract: The primary granule proteins (PGP) of myeloid cells are a source of multiple antigens with immunotherapeutic potential for myeloid leukemias. Therefore, we developed a method to induce T-cell responses to PGP protein sequences. We found that gene-transfected antigen-presenting cells efficiently expand functionally competent PGP-specific CD4 and CD8 T cells. The system was optimized using T-cell responses to autologous CD40-activated B cells (CD40-B) transfected with a cytomegalovirus pp65-encoding expression vector. To generate leukemia-specific T cells, expression vectors encoding the PGP proteinase 3 (PR3), human neutrophil elastase, and cathepsin-G were transfected into CD40-B cells to stimulate post-allogeneic stem cell transplantation T cells from five patients with myeloid and three with lymphoid leukemias. T-cell responses to PGP proteinase 3 and human neutrophil elastase were observed in CD8+ and CD4+ T cells only in patients with myeloid leukemias. T-cell responses against cathepsin-G occurred in both myeloid and lymphoblastic leukemias. T cells from a patient with chronic myelogenous leukemia (CML) and from a posttransplant CML patient, expanded against PGP, produced IFN-gamma or were cytotoxic to the patient's CML cells, demonstrating specific antileukemic efficacy. This study emphasizes the clinical potential of PGP for expansion and adoptive transfer of polyclonal leukemia antigen-specific T cells to treat leukemia.
authors.affiliation: Stem Cell Allotransplant Section, Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: J Joseph
authors.initials: JJ
authors.lastname: Melenhorst
authors.forename: Frank
authors.initials: F
authors.lastname: El Ouriaghli
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kajigaya
authors.forename: Matthias
authors.initials: M
authors.lastname: Grube
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sconocchia
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Hensel
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D056649:Cathepsin G; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression; D018922:HL-60 Cells; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007951:Leukemia, Myeloid / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D053146:Myeloblastin; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D019013:CD40 Antigens; D012333:RNA, Messenger; D023201:CD40 Ligand; D007371:Interferon-gamma; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D053146:Myeloblastin