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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3076-3083. Prepublished online as a Blood First Edition Paper on December 4, 2003; DOI 10.1182/blood-2003-07-2424. This Article Full Text (PDF) All Versions of this Article: 2003-07-2424v1 103/8/3076    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fujiwara, H. Articles by Barrett, A J. Search for Related Content PubMed PubMed Citation Articles by Fujiwara, H. Articles by Barrett, A J. Social Bookmarking                   What's this? Submitted July 21, 2003 Accepted December 2, 2003 Identification and in vitro expansion of CD4+ and CD8+ T cells specific for human neutrophil elastase Hiroshi Fujiwara, Frank El Ouriaghli, Matthias Grube, David A Price, Katayoun Rezvani, Emma Gostick, Giuseppe Sconocchia, Jos Melenhorst, Nancy Hensel, Daniel C Douek, and A John Barrett* Department of Hematology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom * Corresponding author; email: barrettj{at}nhlbi.nih.gov. Human Neutrophil elastase (HNE) and proteinase 3 (PRO3) are myeloid tissue-restricted serine proteases, aberrantly expressed by myeloid leukemia cells. PRO3 and HNE share the PR1 peptide sequence which induces HLA-A*0201-restricted cytotoxic T cells (CTL) with anti-leukemia reactivity. We studied the entire HNE protein for its ability to induce CTL. In an 18 hour culture, HNE-loaded monocytes stimulated significant intracellular IFN- production by CD4+ and CD8+ T-cells in 12/20 and 8/20 normal individuals respectively. Lymphocytes from two HNE responders were pulsed weekly for four weeks to generate HNE specific CTL. One of two HLA-A*0201 negative individuals inhibited the colony formation of HLA-identical chronic myelogenous leukemia progenitor cells (73%, inhibition at 50:1 E:T ratio) indicating that peptides other than PR1 can induce leukemia-reactive CTL. Repetitive stimulations with HNE in two of five HLA-A*0201+ individuals increased PR1 tetramer positive CD8+T-cell frequencies from 0.1% to 0.29% and 0.02% to 0.55% respectively. These CTL recognized PR1 peptide or killed HNE-loaded targets. These results indicate that exogenously processed HNE is a source of PR1 peptide as well as other peptide sequences capable of inducing leukemia-specific CD8+ and CD4+ T cells. HNE could therefore be used in an HLA-unrestricted manner to induce leukemia-reactive CTL for adoptive immunotherapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. J. Melenhorst, P. Scheinberg, P. K. Chattopadhyay, E. Gostick, K. Ladell, M. Roederer, N. F. Hensel, D. C. Douek, A. J. Barrett, and D. A. Price High avidity myeloid leukemia-associated antigen-specific CD8+ T cells preferentially reside in the bone marrow Blood, March 5, 2009; 113(10): 2238 - 2244. [Abstract] [Full Text] [PDF] E. L.J.M. Smits, Z. N. Berneman, and V. F.I. Van Tendeloo Immunotherapy of Acute Myeloid Leukemia: Current Approaches Oncologist, March 1, 2009; 14(3): 240 - 252. [Abstract] [Full Text] [PDF] M. Inokuma, C. dela Rosa, C. Schmitt, P. Haaland, J. Siebert, D. Petry, M. Tang, M. A. Suni, S. A. Ghanekar, D. Gladding, et al. Functional T Cell Responses to Tumor Antigens in Breast Cancer Patients Have a Distinct Phenotype and Cytokine Signature J. Immunol., August 15, 2007; 179(4): 2627 - 2633. [Abstract] [Full Text] [PDF] A. S. M. Yong, K. Rezvani, B. N. Savani, R. Eniafe, S. Mielke, J. M. Goldman, and A. J. Barrett High PR3 or ELA2 expression by CD34+ cells in advanced-phase chronic myeloid leukemia is associated with improved outcome following allogeneic stem cell transplantation and may improve PR1 peptide-driven graft-versus-leukemia effects Blood, July 15, 2007; 110(2): 770 - 775. [Abstract] [Full Text] [PDF] A. S. M. Yong, R. M. Szydlo, J. M. Goldman, J. F. Apperley, and J. V. Melo Molecular profiling of CD34+ cells identifies low expression of CD7, along with high expression of proteinase 3 or elastase, as predictors of longer survival in patients with CML Blood, January 1, 2006; 107(1): 205 - 212. [Abstract] [Full Text] [PDF] H. Fujiwara, J. J. Melenhorst, F. El Ouriaghli, S. Kajigaya, M. Grube, G. Sconocchia, K. Rezvani, D. A. Price, N. F. Hensel, D. C. Douek, et al. 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 Clin. Cancer Res., June 15, 2005; 11(12): 4495 - 4503. [Abstract] [Full Text] [PDF]

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