Specific human cellular immunity to bcr-abl oncogene-derived peptides
Specific human cellular immunity to bcr-abl oncogene-derived peptides
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DOI：
10.1182/blood.v87.9.3587.bloodjournal8793587
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发表时间：
1996-05-01
期刊：
影响因子：
20.3
通讯作者：
Scheinberg, DA
中科院分区：
文献类型：
--
作者：
Bocchia, M;Korontsvit, T;Scheinberg, DA
慢性髓性白血病（CML）细胞以t（9;22）易位为特征，该易位可以编码两种嵌合P210 bcr-abl融合蛋白中的一种，包括b2a2或b3a2外显子连接的产物。连接序列代表潜在的免疫原性肿瘤特异性抗原。尽管它们位于细胞内，但如果从这些独特序列衍生的肽能够被主要的组织相容性复合体分子呈现，则融合蛋白可能被T淋巴细胞免疫识别。我们之前发现，跨越b3a2 CML断点的4个肽，长度为9到11个氨基酸，与纯化的HLA I类分子A3、A11、B8或A3和A11具有高或中等亲和力。我们测试了这些肽在体外hla匹配的健康供体中诱导特异性I类限制性细胞毒性T淋巴细胞（ctl）的能力。此外，研究人员还研究了一个较长的b3a2 cml断点衍生肽，长度为25个氨基酸（b3a2-25），其诱导肽特异性、ii类介导的t细胞增殖的能力。在4个HLA-AB供体中，有4个被诱导CML-A3/ a11肽特异性ctl杀死了异体HLA-AB匹配的肽脉冲白血病细胞系。在三名HLA-A3供者中的两名中，CML-A3/A11肽能够诱导杀死自体和异体hla匹配肽脉冲外周血单个核细胞（PBMC）。CML-AB肽诱导的肽特异性ctl在四名HLA A3供者中的一名中检测。在2例HLA-BB和2例HLA-A11供者中未观察到杀伤。在胸腺嘧啶掺入试验中，对来自7个供体的PBMC进行了抗b3a2-25肽增殖试验。在三个供体中检测到特异性增殖，均为HLA-DR11单倍型。这些数据代表了针对CML bcr-abl癌基因衍生肽的细胞溶解性人类免疫反应的第一个证据，并为开发针对该疾病的基于肽的疫苗提供了理论依据。(C) 1996年由美国血液病学会出版。
Chronic myelogenous leukemia (CML) cells are characterized by a t(9;22) translocation, which can encode one of two chimeric P210 bcr-abl fusion proteins, comprising products of either the b2a2 or the b3a2 exon junction. The junctional sequences represent potentially immunogenic tumor-specific antigens. Despite their intracellular location, the fusion proteins might be recognized immunologically by T lymphocytes if peptides, derived from these unique sequences, are capable of presentation by the major histocompatibility complex molecules. We previously found that four peptides, 9 to 11 amino acids long, spanning the b3a2 CML breakpoint bind with high or intermediate affinity to purified HLA class I molecules A3, A11, B8, or both A3 and A11. We tested the ability of these peptides to elicit specific class I restricted cytotoxic T lymphocytes (CTLs) in vitro in HLA-matched healthy donors. In addition, a longer b3a2 CML-breakpoint-derived peptide, 25 aminoacids in length (b3a2-25), was studied for its ability to induce peptide-specific, class II-mediated, T-cell proliferation. In four of four HLA-AB donors tested, CML-A3/A11-peptide specific CTLs were induced that killed an allogeneic HLA-AB-matched peptide pulsed leukemia cell line. In two of three HLA-A3 donors, the CML-A3/A11 peptide was able to induce killing of autologous and allogeneic HLA-matched peptide-pulsed peripheral blood mononuclear cells (PBMC). CML-AB peptide induced peptide specific CTLs in one of the four HLA A3 donors tested. No killing was observed in two HLA-BB and two HLA-A11 donors. PBMC from seven donors were also tested for anti b3a2-25 peptide proliferation in a thymidine incorporation assay. Specific proliferation was detected in three donors, all of the HLA-DR11 haplotype. These data represent the first evidence of a cytolytic human immune response against CML bcr-abl oncogene-derived peptides and provide a rationale for developing peptide-based vaccines for this disease. (C) 1996 by The American Society of Hematology.