title: Characterization of immunologic properties of a second HLA-A2 epitope from a granule protease in CML patients and HLA-A2 transgenic mice.
abstract: The serine proteases, neutrophil elastase (HNE) and proteinase 3 (PR3), are aberrantly expressed in human myeloid leukemias. T-cell responses to these proteins have been correlated with remission in patients with chronic myeloid leukemia (CML). Human PR3/HNE-specific CD8(+) T cells predominantly recognize a nonameric HLA-A2-restricted T-cell epitope called PR1 which is conserved in both Ags. However, CML patients have CD8(+) T cells in peripheral blood recognizing an additional HLA-A2 epitope termed PR2. To assess immunologic properties of these Ags, novel recombinant vaccinia viruses (rVV) expressing PR3 and HNE were evaluated in HLA-A2 transgenic (Tg) mice (HHDII). Immunization of HHDII mice with rVV-PR3 elicited a robust PR3-specific CD8(+) T-cell response dominated by recognition of PR2, with minimal recognition of the PR1 epitope. This result was unexpected, because the PR2 peptide has been reported to bind poorly to HLA. To account for these findings, we proposed that HHDII mice negatively selected PR1-specific T cells because of the presence of this epitope within murine PR3 and HNE, leading to immunodominance of PR2-specific responses. PR2-specific splenocytes are cytotoxic to targets expressing naturally processed PR3, though PR1-specific splenocytes are not. We conclude that PR2 represents a functional T-cell epitope recognized in mice and human leukemia patients. These studies are registered at www.clinicaltrials.gov as NCT00716911.
authors: Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
authors: Simon F
authors: SF
authors: Lacey
authors: Corinna
authors: C
authors: La Rosa
authors: Teodora
authors: T
authors: Kaltcheva
authors: Tumul
authors: T
authors: Srivastava
authors: Aprille
authors: A
authors: Seidel
authors: Wendi
authors: W
authors: Zhou
authors: Ravindra
authors: R
authors: Rawal
authors: Katharine
authors: K
authors: Hagen
authors: Aparna
authors: A
authors: Krishnan
authors: Jeff
authors: J
authors: Longmate
authors: Helen A
authors: HA
authors: Andersson
authors: Lisa
authors: L
authors: St John
authors: Ravi
authors: R
authors: Bhatia
authors: Vinod
authors: V
authors: Pullarkat
authors: Stephen J
authors: SJ
authors: Forman
authors: Laurence J N
authors: LJ
authors: Cooper
authors: Jeffrey
authors: J
authors: Molldrem
authors: Don J
authors: DJ
authors: Diamond
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000628:therapy; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D053146:Myeloblastin / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D011994:Recombinant Proteins; D019272:Leukocyte Elastase; D053146:Myeloblastin