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[Cancer Research 59, 2675-2681, June 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 2675-2681, June 1, 1999]
© 1999 American Association for Cancer Research

Immunology

A PR1-Human Leukocyte Antigen-A2 Tetramer Can Be Used to Isolate Low-Frequency Cytotoxic T Lymphocytes from Healthy Donors That Selectively Lyse Chronic Myelogenous Leukemia1

Jeffrey J. Molldrem2, Peter P. Lee, Changqing Wang, Richard E. Champlin and Mark M. Davis

Transplantation Immunology Section, Blood and Marrow Transplant Department, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095 [J. J. M., C. W., R. E. C.], and Howard Hughes Medical Institute, Department of Microbiology and Immunology, Stanford University, Palo Alto, California, 94305 [P. P. L., M. M. D.]

We previously showed (E. Clave et al., J. Immunother., 22: 1–6, 1999; J. Molldrem et al., Blood, 88: 2450–2457, 1996) that PR1, a human-lymphocyte-antigen (HLA)-A2.1-restricted peptide from proteinase 3, could be used to elicit CTLs from normal individuals. These CTLs showed HLA-restricted cytotoxicity and colony inhibition of myeloid leukemia cells that overexpress proteinase 3. In this study, we constructed a phycoerythrin-labeled PR1-HLA-A2 tetramer to identify PR1-specific CTLs by flow cytometry. No peripheral blood lymphocytes from three HLA-2.1+ donors stained with the tetramer, but, after 20 days in culture with weekly PR1 stimulation, 2–8% became tetramer+. Tetramer staining identified up to 40-fold more PR1-specific CTLs than were identified by limiting dilution analysis and correlated better with lysis of PR1-coated T2 cells (R2 = 0.95 versus R2 = 0.76). Tetramer+ CTLs were memory phenotype (91% CD45RO+), and most (58% CD95+) were activated. Tetramer-sorted allogeneic CTLs produced 83% lysis of HLA-A2.1+ chronic myelogenous leukemia (CML) blasts at an E:T ratio of 2.5:1, compared with 23% lysis by nonsorted CTLs, with no background lysis of HLA-A2.1+ normal cells. Cytoplasmic proteinase-3 expression was one log greater in CML blasts than in normal granulocytes. These results show that a PR1-HLA-A2 tetramer can be used to identify and select CTLs from normal donors that preferentially lyse CML cells, which could be used for leukemia-specific adoptive immunotherapy.




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Copyright © 1999 by the American Association for Cancer Research.