Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DOβ as a novel target for multiple myeloma.
Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DOβ as a novel target for multiple myeloma.
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DOI：
10.1111/bjh.12544
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发表时间：
2013-11
影响因子：
6.5
通讯作者：
Sasada T
中科院分区：
文献类型：
--
作者：
Kang YJ;Zeng W;Song W;Reinhold B;Choi J;Brusic V;Yamashita T;Munshi A;Li C;Minvielle S;Anderson KC;Munshi N;Reinherz EL;Sasada T
尽管最近开发了针对多发性骨髓瘤（MM）的有效治疗剂，但仍有待开发新的治疗方法，包括免疫疗法。本研究从B细胞特异性分子HLA-DOβ（DOB）中筛选出一个新的HLA-A*0201（HLAA 2）限制性细胞毒性T淋巴细胞（CTL）表位作为MM的潜在靶点。从HLA-DOB的氨基酸序列中预测了25个肽与HLA-A2结合。当在用HLA-DOB cDNA免疫的HLA-A2转基因小鼠中筛选免疫原性时，4种肽基本上是免疫原性的。通过对从MM细胞系的HLA-A2免疫沉淀物洗脱的肽进行质谱分析，仅确认了两个表位HLA-DOB 232 -240（FLLGLIFLL）和HLA-DOB 185 -193（VMLEMTPEL）在细胞表面上的物理存在。当健康供体血液在体外用这两种肽重复刺激并通过抗原特异性γ-干扰素分泌评估时，HLA-DOB 232 -240比HLA-DOB 185 -193更具免疫原性。此外，HLA-DOB 232 -240特异性CTL，而不是HLA-DOB 185 -193特异性CTL，对同时表达HLA-A2和HLA-DOB的MM细胞系表现出主要组织相容性复合体I类限制性反应。综上所述，基于HLA-DOB 232 -240在肿瘤细胞表面的物理存在和高免疫原性，HLA-DOB 232 -240可能用于开发针对MM的新型免疫疗法。
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 (HLAA2)-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 HLADOB 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.
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影响因子：
6.5
作者：
Bae, Jooeun;Tai, Yu-Tzu;Munshi, Nikhil C.
通讯作者：
Munshi, Nikhil C.
影响因子：
4.6
作者：
Maecker, B;von Bergwelt-Baildon, MS;Schultze, JL
通讯作者：
Schultze, JL
影响因子：
7.4
作者：
Reinhold, Bruce;Keskin, Derin B.;Reinherz, Ellis L.
通讯作者：
Reinherz, Ellis L.
影响因子：
11.5
作者：
Palumbo, Antonio;Attal, Michel;Roussel, Murielle
通讯作者：
Roussel, Murielle
影响因子：
5.8
作者：
Anderson, Karen S.;Zeng, Wanyong;Reinherz, Ellis L.
通讯作者：
Reinherz, Ellis L.