Induction of BCR-ABL-specific immunity following vaccination with chaperone-rich cell lysates derived from BCR-ABL+ tumor cells.
Induction of BCR-ABL-specific immunity following vaccination with chaperone-rich cell lysates derived from BCR-ABL+ tumor cells.
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DOI：
10.1182/blood-2004-05-1915
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发表时间：
2005-03
期刊：
影响因子：
20.3
通讯作者：
Yi Zeng;M. Graner;S. Thompson;M. Marron;Emmanuel Katsanis
中科院分区：
文献类型：
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作者：
Yi Zeng;M. Graner;S. Thompson;M. Marron;Emmanuel Katsanis
我们之前曾报道过，源自 BCR-ABL+ 12B1 白血病的伴侣细胞裂解物 (CRCL) 可以激活树突状细胞 (DC) 并刺激白血病特异性免疫反应。由于 CRCL 含有多种热休克/伴侣蛋白，我们推测从 BCR-ABL+ 白血病获得的 CRCL 很可能伴侣 BCR-ABL 衍生的融合肽，并且用 12B1 CRCL 脉冲的 DC 可以将 BCR-ABL 融合肽交叉呈递给 T 细胞。我们发现，当用 BCR-ABL 肽 GFKQSSKAL 重新刺激时，接种 BCR-ABL+ 白血病来源的 CRCL 的小鼠的脾细胞会分泌干扰素-γ (IFN-γ)，这表明 BCR-ABL 肽受到白血病来源的 CRCL 的陪伴。接下来，我们从 12B1 白血病衍生的 CRCL 中洗脱肽，并使用高压液相色谱 (HPLC) 组分重新刺激从接种 DC/GFKQSSKAL 或 DC/12B1 CRCL 疫苗的小鼠中收获的脾细胞。我们发现源自 12B1 CRCL 和“折射”GFKQSSKAL 的相同肽级分刺激 IFN-γ 产生，表明 12B1 CRCL 的肽库中存在 BCR-ABL 肽。我们还证明，用负载有白血病来源的 CRCL 的 DC 进行免疫可在体内诱导 BCR-ABL 特异性细胞毒性 T 淋巴细胞 (CTL)。此外，与用 BCR-ABL 肽脉冲的 DC 免疫的小鼠 (20%) 相比，用 12B1 衍生的 CRCL 脉冲的 DC 免疫的小鼠具有更高的存活率 (60%)，这表明 CRCL 疫苗在单独的肽疫苗接种之外提供了额外的免疫刺激。
We have previously reported that chaperonerich cell lysates (CRCL) derived from the BCR-ABL+ 12B1 leukemia activate dendritic cells (DCs) and stimulate leukemia-specific immune responses. Because CRCL contain a variety of heat shock/chaperone proteins, we theorized that CRCL obtained from BCR-ABL+ leukemias are likely to chaperone BCR-ABL-derived fusion peptides and that DCs pulsed with 12B1 CRCL could cross-present BCR-ABL fusion peptides to T cells. We found that splenocytes from mice vaccinated with BCR-ABL+ leukemia-derived CRCL secreted interferon-gamma (IFN-gamma) when restimulated with a BCR-ABL peptide, GFKQSSKAL, indicating that BCR-ABL peptides are chaperoned by leukemia-derived CRCL. We next eluted peptides from 12B1 leukemia-derived CRCL and used high-pressure liquid chromatography (HPLC) fractions to restimulate splenocytes harvested from mice vaccinated with DC/GFKQSSKAL or DC/12B1 CRCL. We found that the same peptide fractions derived from 12B1 CRCL and from "refractionated" GFKQSSKAL stimulated IFN-gamma production, suggesting the presence of BCR-ABL peptides in the peptide repertoire of 12B1 CRCL. We also demonstrated that immunization with DCs loaded with leukemia-derived CRCL induced BCR-ABL-specific cytotoxic T lymphocytes (CTLs) in vivo. Moreover, mice immunized with DCs pulsed with 12B1-derived CRCL had superior survival (60%) when compared with those immunized with DCs pulsed with BCR-ABL peptide (20%), indicating that CRCL vaccines provide additional immune stimulus over and above individual peptide vaccination.