Efficacious immune therapy in chronic myelogenous leukemia (CML) recognizes antigens that are expressed on CML progenitor cells.
Efficacious immune therapy in chronic myelogenous leukemia (CML) recognizes antigens that are expressed on CML progenitor cells.
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DOI：
10.1158/0008-5472.can-09-2303
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Wu CJ
中科院分区：
文献类型：
--
作者：
Biernacki MA;Marina O;Zhang W;Liu F;Bruns I;Cai A;Neuberg D;Canning CM;Alyea EP;Soiffer RJ;Brusic V;Ritz J;Wu CJ
供者淋巴细胞输注(DLI)等以移植物抗白血病(GVL)为基础的治疗慢性粒细胞白血病(CML)的疗效可能源于自身更新的CML祖细胞的免疫靶向。在DLI后获得持久缓解的患者在治疗后发展为显著的B细胞淋巴细胞增多症，这在对DLI无效的患者中没有观察到。为了确定这种B细胞反应的靶点，我们探索了两个互补的免疫蛋白质组平台，一个噬菌体表达文库和一个高密度蛋白芯片，使用来自7名临床上明显的GVL且在DLI后没有移植物抗宿主病的CML患者的血浆免疫球蛋白。总体而言，62种抗原在DLI后与DLI前相比可引起更大的反应性。在HG-FOCUS和HG-U133A Affymetrix芯片分析中，CML CD34+细胞中可检测到70%以上的抗原，这表明在恶性前体细胞中的表达是DLI抗体靶标的共同特征。三种靶抗原(RAB38、TBCE和DUSP12)在CML中的转录和蛋白表达均高于正常CD34+细胞。加在一起，在21名对治疗有临床反应的CML患者中，他们一直在另外18名患者中引发抗体反应，但在正常捐赠者中没有，在没有CML的患者中也很少。因此，治疗DLI反应的免疫学靶点包括多个CML祖细胞表达的抗原，这些抗原可能代表用于疫苗接种和/或监测旨在消除髓系白血病干细胞的免疫治疗策略的潜在免疫原。
The curative effect of existing graft-versus-leukemia (GvL)-based therapies such as donor lymphocyte infusion (DLI) for chronic myeloid leukemia (CML) may result from immunologic targeting of self-renewing CML progenitor cells. Patients who achieved durable remission following DLI developed a significant B cell lymphocytosis after treatment, which was not observed in patients unresponsive to DLI. To identify targets of this B cell response, we probed two complementary immunoproteomic platforms, a bacteriophage expression library and a high-density protein microarray, using plasma immunoglobulin from seven CML patients with clinically apparent GvL and without graft-versus-host disease after DLI. In total, 62 antigens elicited greater reactivity from post-DLI versus pre-DLI plasma. More than 70% of the antigens were detectable in CML CD34+ cells in an analysis of HG-FOCUS and HG-U133A Affymetrix microarrays, suggesting that expression in malignant progenitor cells is a feature common to antibody targets of DLI. Higher transcript and protein expression in CML compared to normal CD34+ cells was confirmed for three target antigens (RAB38, TBCE, and DUSP12). Together, they consistently elicited antibody responses in an additional 18 of 21 CML patients with clinical responses to therapy, but not in normal donors and only rarely in patients without CML. Immunologic targets of curative DLI responses thus comprise multiple CML progenitor cell-expressed antigens that may represent potential immunogens for vaccination and/or monitoring of immunotherapeutic strategies designed to eliminate myeloid leukemia stem cells.