This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rezvani, K. Articles by Barrett, A. J. Search for Related Content PubMed PubMed Citation Articles by Rezvani, K. Articles by Barrett, A. J.

T-Cell Responses Directed against Multiple HLA-A*0201-Restricted Epitopes Derived from Wilms' Tumor 1 Protein in Patients with Leukemia and Healthy Donors: Identification, Quantification, and Characterization

Authors' Affiliations: ¹ Stem Cell Allotransplantation Section, Hematology Branch, National Heart Lung Blood Institute and ² Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland; and ³ Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom

Requests for reprints: Katayoun Rezvani, National Heart Lung Blood Institute, NIH, Room 3E-5288, Building 10, 900 Rockville Pike, Bethesda, MD 20892. Phone: 301-435-4107; Fax: 301-480-2664; E-mail: rezvanik{at}nhlbi.nih.gov.

Purpose: Antigens derived from the Wilms' tumor (WT1) protein, which is overexpressed in leukemias, are attractive targets for immunotherapy. Four HLA-A*0201-restricted WT1-derived epitopes have been identified: WT37, WT126, WT187, and WT235. We determined the natural immunogenecity of these antigens in patients with hematologic malignancies and healthy donor.

Experimental Design: To detect very low frequencies of WT1-specific CD8⁺ T cells, we used quantitative reverse transcription-PCR to measure IFN- mRNA production by WT1 peptide–pulsed CD8⁺ T cells from 12 healthy donors, 8 patients with chronic myelogenous leukemia, 6 patients with acute myelogenous leukemia, and 8 patients with acute lymphoblastic leukemia.

Results: Responses were detected in 5 of 8 chronic myelogenous leukemia patients, 4 of 6 patients with acute myelogenous leukemia, and 7 of 12 healthy donors. No responses were detected in patients with acute lymphoblastic leukemia. The magnitude and extent of these CD8⁺ T-cell responses was greater in patients with myeloid leukemias than in healthy donors. Clonotypic analysis of WT1-specific CD8⁺ T cells directly ex vivo in one case showed that this naturally occurring population was oligoclonal. Using fluorescent peptide-MHC class I tetramers incorporating mutations in the 3 domain (D227K/T228A) that abrogate binding to the CD8 coreceptor, we were able to confirm the presence of high-avidity T-cell clones within the antigen-specific repertoire.

Conclusion: The natural occurrence of high-avidity WT1-specific CD8⁺ T cells in the periphery could facilitate vaccination strategies to expand immune responses against myeloid leukemias.

This article has been cited by other articles:

				K. Rezvani, A. S. M. Yong, S. Mielke, B. N. Savani, L. Musse, J. Superata, B. Jafarpour, C. Boss, and A. J. Barrett Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies Blood, January 1, 2008; 111(1): 236 - 242. [Abstract] [Full Text] [PDF]

				K. Rezvani, A. S. M. Yong, B. N. Savani, S. Mielke, K. Keyvanfar, E. Gostick, D. A. Price, D. C. Douek, and A. J. Barrett Graft-versus-leukemia effects associated with detectable Wilms tumor-1 specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia Blood, September 15, 2007; 110(6): 1924 - 1932. [Abstract] [Full Text] [PDF]