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.
| Autor: | Rezvani K; Stem Cell Allotransplantation Section, Hematology Branch, National Heart Lung Blood Institute and Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA. rezvanik@nhlbi.nih.gov, Brenchley JM, Price DA, Kilical Y, Gostick E, Sewell AK, Li J, Mielke S, Douek DC, Barrett AJ |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2005 Dec 15; Vol. 11 (24 Pt 1), pp. 8799-807. |
| DOI: | 10.1158/1078-0432.CCR-05-1314 |
| Abstrakt: | 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-gamma 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 alpha3 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. |
| Databáze: | MEDLINE |
| Externí odkaz: |
|