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Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units.

Abstract
We previously showed that a peptide (PR1) derived from the primary granule enzyme proteinase 3 induced peptide specific cytotoxic T lymphocytes (CTL) in a normal HLA-A2.1+ individual. These CTL showed HLA-restricted cytotoxicity to myeloid leukemias (which overexpress proteinase 3). To further investigate their antileukemic potential, we studied the ability of PR1-specific CTL, derived from two HLA-A2.1+ normal individuals, to inhibit colony-forming unit granulocyte-macrophage (CFU-GM) from normal and leukemic individuals. CTL from 20 day PR1 peptide-pulsed lymphocyte cultures showed 89% to 98% HLA-A2.1-restricted colony inhibition of chronic myeloid leukemia targets. Colony formation in normal HLA-A2.1+ bone marrow or HLA-A2.1- CML cells was not inhibited. Sequencing of the exon encoding PR1 showed that colony inhibition was not caused by polymorphic differences in proteinase 3 between effectors and targets. Analysis by flow cytometry showed that proteinase 3 was overexpressed in the leukemia targets compared with normal marrow targets (median channel fluorescence 1,399 v 298, P = .009). These results show that PR1-specific allogeneic T cells preferentially inhibit leukemic CFU-GM based on overexpression of proteinase 3, and that proteinase 3-specific CTL could be used for leukemia-specific adoptive immunotherapy.
AuthorsJ J Molldrem, E Clave, Y Z Jiang, D Mavroudis, A Raptis, N Hensel, V Agarwala, A J Barrett
JournalBlood (Blood) Vol. 90 Issue 7 Pg. 2529-34 (Oct 01 1997) ISSN: 0006-4971 [Print] United States
PMID9326217 (Publication Type: Journal Article)
Chemical References
  • HLA-A2 Antigen
  • Neoplasm Proteins
  • Peptide Fragments
  • Serine Endopeptidases
  • Myeloblastin
Topics
  • Bone Marrow (pathology)
  • Cells, Cultured
  • Cytotoxicity, Immunologic
  • Exons (genetics)
  • HLA-A2 Antigen (immunology)
  • Humans
  • Immunotherapy, Adoptive
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (immunology, pathology)
  • Myeloblastin
  • Neoplasm Proteins (chemistry, genetics, immunology)
  • Neoplastic Stem Cells (enzymology, immunology)
  • Peptide Fragments (genetics, immunology)
  • Serine Endopeptidases (chemistry, genetics, immunology)
  • T-Lymphocytes, Cytotoxic (immunology)
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay

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