Immunity to WT1 in the animal model and in patients with acute myeloid leukemia
Immunity to WT1 in the animal model and in patients with acute myeloid leukemia
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DOI：
10.1182/blood.v96.4.1480.h8001480_1480_1489
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发表时间：
2000-08-15
期刊：
影响因子：
20.3
通讯作者：
Cheever, MA
中科院分区：
文献类型：
--
作者：
Gaiger, A;Reese, V;Cheever, MA
维尔姆斯肿瘤 (WT1) 基因参与白血病发生，并在人类大多数类型的白血病中过度表达。 WT1 在人类多种类型的肺癌、甲状腺癌、乳腺癌、睾丸癌、卵巢癌以及黑色素瘤中也可检测到。初步研究评估了是否可以在小鼠中引发针对小鼠 WT1 的免疫反应。鼠类和人类 WT1 相似。因此，小鼠模型可能会解决开发 WT1 疫苗的许多关键问题。 C57/BL6 (B6) 小鼠被注射来自 WT1 天然序列的合成肽，该肽含有与主要组织相容性 (MHC) II 类分子结合的基序。免疫诱导对免疫WT1肽具有特异性的辅助T细胞反应和对WT1蛋白具有特异性的抗体反应。对多种小鼠癌细胞系的筛选发现了 2 种小鼠癌症：TRAMP-C 和 BLKSV40，它们“自然”过度表达 WT1。用 MHC I 类结合肽进行免疫诱导产生 WT1 肽特异性细胞毒性 T 淋巴细胞 (CTL)，该细胞特异性裂解 TRAMP-C 和 BLKSV40。通过冷靶抑制证实了 WT1 裂解的特异性。 WT1肽免疫动物的组织病理学评估未发现毒性。 WT1肽免疫对体内TRAMP-C肿瘤生长没有显示出任何影响。对 B6 小鼠进行同源 TRAMP-C 免疫可引发 WT1 特异性抗体，证明 WT1 在癌细胞中具有免疫原性。为了评估 WT1 在人类中是否可能具有类似的免疫原性，对白血病患者的血清中预先存在的抗体反应进行了评估，蛋白质印迹分析显示，在 18 名急性髓系白血病 (AML) 患者中，有 3 名患者的血清中存在针对 WT1 蛋白 N 末端部分的 WT1 特异性抗体。 （血液。2000；96：1480-1489）(C) 2000 年，美国血液学会。
The Wilms' tumor (WT1) gene participates in leukemogenesis and is overexpressed in most types of leukemia in humans. WT1 is also detectable in many types of lung, thyroid, breast, testicular and ovarian cancers and melanoma in humans. Initial studies evaluated whether immune responses to murine WT1 can be elicited in mice. Murine and human WT1 are similar. Thus, mouse models might lead to resolution of many of the critical issues for developing WT1 vaccines. C57/BL6 (B6) mice were injected with synthetic peptides from the natural sequence of WT1 containing motifs for binding to major histocompatibility (MHC) class II molecules. Immunization induced helper T-cell responses specific for the immunizing WT1 peptides and antibody responses specific for WT1 protein. Screening of multiple murine cancer cell lines identified 2 murine cancers, TRAMP-C and BLKSV40, that "naturally" overexpress WT1. Immunization with MHC class I binding peptides induced WT1 peptide-specific cytotoxic T-lymphocyte (CTL) that specifically lysed TRAMP-C and BLKSV40. WT1 specificity of lysis was confirmed by cold target inhibition. No toxicity was noted by histopathologic evaluation in the WT1 peptide-immunized animals. WT1 peptide immunization did not show any effect on TRAMP-C tumor growth in vivo. Immunization of B6 mice to syngeneic TRAMP-C elicited WT1-specific antibody, demonstrating that WT1 can be immunogenic in the context of cancer cells. To evaluate whether WT1 might be similarly immunogenic in humans, serum from patients with leukemia was evaluated for preexisting antibody responses, Western blot analyses showed WT1-specific antibodies directed against the N-terminus portion of the WT1 protein in the sera of 3 of 18 patients with acute myeloid leukemia (AML). (Blood. 2000;96:1480-1489) (C) 2000 by The American Society of Hematology.