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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 (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 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 Social Bookmarking                   What's this? Submitted February 15, 2002 Accepted September 3, 2002 Allo-restricted 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 Departments of Haematology and Immunology, Imperial College School of Medicine, London, United Kingdom Center for Cell and Gene Therapy, Texas Children's Cancer Center, Houston, TX, USA * Corresponding author; email: pjamroli{at}txccc.org. Recent advances have made haplo-identical transplantation for leukemia feasible, but the rigorous T-cell depletion used contributes to high relapse rates. We have attempted to improve the graft-versus-leukemia effect by generating allo-restricted CTL directed against human CD45. Such CTL should recognise patient hematopoietic cells including leukemia, enhancing donor cell engraftment and improving the GVL effect, but should not recognise host non-hematopoietic 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 -ve donors by sequential stimulation with peptide-pulsed HLA-A2 +ve stimulators, and the lines obtained were screened for peptide-specific cytotoxicity. Using one of these peptides (P1218), it was possible to generate peptide-specific, allo--restricted CTL in 3 out of 7 responders. P1218-specific CTL lines show potent cytotoxicity against hematopoietic cell lines co-expressing both HLA-A2 and CD45 but not CD45 loss variants. Studies with stable transfectants of 293 cells demonstrated recognition by P1218-specific CTL of endogenously expressed CD45. Likewise P1218-specific CTL recognized peripheral blood mononuclear cells from HLA-A2 +ve patients with CML and leukemic blasts in HLA-A2 +ve patients with AML, but were unable to lyse HLA-A2 +ve fibroblasts or HLA-A2 -ve normal PBMC. Co-culture of CD34+ve PBMC/BMMNC with P1218 specific CTL significantly inhibited CFU-GM colony formation in both HLA-A2+ve normal individuals and CML patients without significant inhibition in HLA-A2-ve normal controls. These studies demonstrate that P1218-specific CTL have potent activity against leukemic progenitors and suggest that adoptive immunotherapy with allo-restricted CTL directed against CD45 epitopes may be useful in restoring the graft-versus-leukemia effect post HLA-A2-mismatched haplo-identical transplantation. Further, since P1218-specific CTL also recognize normal HLA-A2+ve progenitors, such CTL could potentially also contribute to host myeloablation and enhance donor cell engraftment. 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