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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-02-0525. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-02-0525v1 101/3/1007    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Amrolia, P. J. Articles by Stauss, H. J. Search for Related Content PubMed PubMed Citation Articles by Amrolia, P. J. Articles by Stauss, H. J. Related Collections Immunobiology Transplantation Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 February 2003, Vol. 101, No. 3, pp. 1007-1014 IMMUNOBIOLOGY Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity Persis J. Amrolia, Steven D. Reid, Liquan Gao, Beate Schultheis, Gianpietro Dotti, Malcolm K. Brenner, Junia V. Melo, John M. Goldman, and Hans J. Stauss From the Departments of Haematology and Immunology, Imperial College School of Medicine, London, United Kingdom; and the Center for Cell and Gene Therapy, Texas Children's Cancer Center, Houston. Recent advances have made haploidentical transplantation for leukemia feasible, but the rigorous T-cell depletion used contributes to the high relapse rates observed. We have attempted to improve the graft-versus-leukemia (GVL) effect by generating allorestricted cytotoxic T lymphocytes (CTLs) directed against human CD45. Such CTLs should recognize patient hematopoietic cells including leukemia, enhancing donor cell engraftment and improving the GVL effect, but they should not recognize host nonhematopoietic tissues or donor cells from the graft. Using the T2 binding assay, 4 CD45-derived peptides were found to bind HLA-A2 molecules. These peptides were used to generate cytotoxic T-cell lines from HLA-A2 donors by sequential stimulation with peptide-pulsed HLA-A2+ stimulators, and the lines obtained were screened for peptide-specific cytotoxicity. Using one of these peptides (P1218), it was possible to generate peptide-specific, allorestricted CTLs in 3 of 7 responders. P1218-specific CTL lines show potent cytotoxicity against hematopoietic cell lines coexpressing HLA-A2 and CD45 but not CD45 loss variants. Studies with stable transfectants of 293 cells demonstrated recognition by P1218-specific CTLs of endogenously expressed CD45. Likewise P1218-specific CTLs recognized peripheral blood mononuclear cells (PBMCs) from HLA-A2+ patients with chronic myeloid leukemia (CML) and leukemic blasts in HLA-A2+ patients with acute myeloid leukemia (AML), but they were unable to lyse HLA-A2+ fibroblasts or HLA-A2 normal PBMCs. Coculture of CD34+ PBMCs and bone marrow mononuclear cells (BMMCs) with P1218-specific CTL significantly inhibited colony-forming unit-granulocyte macrophage (CFU-GM) formation in HLA-A2+ healthy controls and CML patients but resulted in no significant inhibition in HLA-A2 healthy controls. These studies demonstrate that P1218-specific cytotoxic T lymphocytes (CTLs) have potent activity against leukemic progenitors and suggest that adoptive immunotherapy with allorestricted CTLs directed against CD45 epitopes may be useful in restoring the GVL effect after HLA-A2-mismatched haploidentical transplantation. Further, because P1218-specific CTLs also recognize healthy HLA-A2+ progenitors, such CTLs could also contribute to host myeloablation and enhance donor cell engraftment. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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] D. D. Sloan, J.-Y. Han, T. K. Sandifer, M. Stewart, A. J. Hinz, M. Yoon, D. C. Johnson, P. G. Spear, and K. R. Jerome Inhibition of TCR Signaling by Herpes Simplex Virus J. Immunol., February 1, 2006; 176(3): 1825 - 1833. [Abstract] [Full Text] [PDF] A. M. E. Whitelegg, L. E. M. Oosten, S. Jordan, M. Kester, A. G. S. van Halteren, J. A. Madrigal, E. Goulmy, and L. D. 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