T-Cell Responses Directed against Multiple HLA-A*0201-Restricted Epitopes Derived from Wilms’ Tumor 1 Protein in Patients with Leukemia and Healthy Do

Posted by rob on December 22, 2005 under Uncategorized | Be the First to Comment

Rezvani K, Brenchley JM, Price DA, Kilical Y, Gostick E, Sewell AK, Li J, Mielke S, Douek DC, Barrett AJ

Clin Cancer Res. 2005 Dec 15; 11(24): 8799-8807

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.

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