Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DOβ as a novel target for multiple myeloma.

Abstract

Despite the recent development of effective therapeutic agents against multiple myeloma (MM), new therapeutic approaches, including immunotherapies, remain to be developed. Here we identified novel human leucocyte antigen (HLA)-A*0201 (HLA-A2)-restricted cytotoxic T lymphocyte (CTL) epitopes from a B cell specific molecule HLA-DOβ (DOB) as a potential target for MM. By DNA microarray analysis, the HLA-DOB expression in MM cells was significantly higher than that in normal plasma cells. Twenty-five peptides were predicted to bind to HLA-A2 from the amino acid sequence of HLA-DOB. When screened for the immunogenicity in HLA-A2-transgenic mice immunized with HLA-DOB cDNA, 4 peptides were substantially immunogenic. By mass spectrometry analysis of peptides eluted from HLA-A2-immunoprecipitates of MM cell lines, only two epitopes, HLA-DOB232-240 (FLLGLIFLL) and HLA-DOB185-193 (VMLEMTPEL), were confirmed for their physical presence on cell surface. When healthy donor blood was repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific γ-interferon secretion, HLA-DOB232-240 was more immunogenic than HLA-DOB185-193 . Additionally, the HLA-DOB232-240 -specific CTLs, but not the HLA-DOB185-193 -specific CTLs, displayed an major histocompatibility complex class I-restricted reactivity against MM cell lines expressing both HLA-A2 and HLA-DOB. Taken together, based on the physical presence on tumour cell surface and high immunogenicity, HLA-DOB232-240 might be useful for developing a novel immunotherapy against MM.

• Authors: Yoon Joong Kang, Wanyong Zeng, Weihua Song, Bruce Reinhold, Jaewon Choi, Vladimir Brusic, Takuto Yamashita, Aditya Munshi, Cheng Li, Stephane Minvielle, Kenneth C Anderson, Nikhil Munshi, Ellis L Reinherz, Tetsuro Sasada
• Journal: British journal of haematology (Br J Haematol) Vol. 163 Issue 3 Pg. 343-51 (Nov 2013) ISSN: 1365-2141 [Electronic] England
• PMID: 24032635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons Ltd.

Chemical References

• DNA, Complementary
• Epitopes, T-Lymphocyte
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• HLA-D Antigens
• HLA-DO antigens
• Peptide Fragments
• Vaccines, DNA

Topics

• Amino Acid Sequence
• Animals
• Cytotoxicity, Immunologic
• DNA, Complementary (genetics, immunology)
• Epitopes, T-Lymphocyte (immunology)
• Genes, MHC Class II
• HLA-A2 Antigen (immunology)
• HLA-D Antigens (genetics, immunology)
• Humans
• Immunization
• Immunotherapy (methods)
• Interferon-gamma Release Tests
• K562 Cells
• Mice
• Mice, Transgenic
• Molecular Sequence Data
• Molecular Targeted Therapy (methods)
• Multiple Myeloma (immunology, therapy)
• Oligonucleotide Array Sequence Analysis
• Peptide Fragments (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Transfection
• Vaccines, DNA (immunology)