Quan Le1, J. Joseph Melenhorst1, Nancy Hensel1, Rhoda Eniafe1, A. John Barrett1
1Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
Tóm tắt
Abstract
The detection of naturally occurring T cells responding to proteins overexpressed in myeloid leukemia suggests that vaccines could boost the immune response to leukemia and achieve disease control. Human neutrophil elastase (HNE) is a myeloid-restricted protein highly expressed in myeloid leukemia cells. HNE protein can induce both CD4+ and CD8+ T cell responses in healthy individuals including HLA-A*0201 negative individuals. To develop HNE protein vaccine, and to identify major histocompatibility complex (MHC) class II restricted or HLA-A*0201 negative MHC class I restricted epitopes in HNE, we stimulated peripherial blood mononuclear cells (PBMC) from 6 myeloid leukemia pre-transplant patients with purified full length HNE protein. HNE protein induced a response in CD4+ and CD8+ T cells from 4 patients with acute myeloid leukemia (AML), as measured by IFN-γ protein expression in flow cytometric assay. However, no response was detected in CD4+ and CD8+ T cells from 2 pre-transplant patients with chronic myeloid leukemia (CML). Responses of CD4+ and CD8+ T cells to HNE protein stimulation were enhanced by HNE expressing antigen-presenting T cells (T-APC), as measured by flow cytometric assay. HNE protein induced significant IFN-γ expression in CD4+ and CD8+ T cells at 540X and 10X above background in an (HLA-A11, 31) AML patient (patient #1 in the figure), and at 6X and 3.5X above background in an (HLA-A*0205, 03*) AML patient (patient #2 in the figure), as measured by quantitative Real-Time RT-PCR assay (QRT-PCR). HNE protein also induced significant IL-2 production in CD4+ and CD8+ T cells at 7.7X and 6.1X above background in patient #1. Finally, we showed by QRT-PCR that the T cell responses to HNE protein stimulation were associated with the levels of HNE gene transcripts in the PBMC. Thus we found that full-length HNE protein stimulated both CD4+ and CD8+ T cell responses in HLA-A*0201 negative patients with AML. These results provide the rationale for using the full-length HNE protein to vaccinate patients with myeloid leukemias pre- or post-stem cell transplantation to improve graft-versus-leukemia effects.
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