CD40 ligand induces an antileukemia immune response in vivo
CD40 ligand induces an antileukemia immune response in vivo
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DOI：
10.1182/blood.v90.5.1927
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发表时间：
1997-09-01
期刊：
影响因子：
20.3
通讯作者：
Brenner, M
中科院分区：
文献类型：
--
作者：
Dilloo, D;Brown, M;Brenner, M
白血病细胞可能表达与 I 类和 II 类主要组织相容性复合体 (MHC) 分子相关的肿瘤特异性抗原。然而，缺乏常规共刺激分子的表达意味着这些细胞倾向于诱导特异性 T 细胞无反应而不是激活。 CD40 配体 (CD40L) 是一种共刺激分子，可直接激活 T 细胞，并可促进表达 CD40 的细胞（包括专业抗原呈递细胞和来自许多患者的 B 急性淋巴细胞白血病 (ALL) 细胞）的抗原呈递。我们在肿瘤治疗模型中使用CD40（+）鼠淋巴母细胞（A20）白血病和CD40（-）骨髓母细胞（WEHI-3）白血病确定CD40L的转基因表达是否可以增强抗白血病免疫反应。在 CD40L 存在的情况下注射其他非免疫原性的 A20 细胞诱导了针对远处预先存在的 A20 肿瘤的免疫反应。此外，转基因白细胞介素2 (IL-2) 的局部分泌进一步增强了诱导的抗白血病反应，并增强了对先前存在的肿瘤的保护。在离体研究中，A20 细胞的 CD40 激活通过上调 B7.1 (CD80)、I 类和 II 类 MHC 分子的表达来增强 A20 细胞的抗原呈递潜力，并增加 fas 抗原的表达。转基因 CD40L 未能预防 CD40(-) WEHI 成髓细胞白血病，进一步强调了 CD40 激活对其产生的抗肿瘤反应的重要性。耗竭研究表明，针对 A20 细胞的保护作用是由 CD4(+) 和 CD8(+) T 淋巴细胞组合以及自然杀伤 (NK) 细胞介导的。这些结果表明了一种使CD40(+)白血病细胞在体内具有免疫原性的方法。 (C) 1997 年，美国血液学会。
Leukemia cells may express tumor specific antigens in association with Class I and II major histocompatability complex (MHC) molecules. However, lack of expression of conventional costimulator molecules means that these cells tend to induce specific T-cell anergy rather than activation. CD40 ligand (CD40L) is a costimulator molecule that directly activates T cells and may promote antigen presentation by CD40-expressing cells, which include professional antigen presenting cells and B-acute lymphoblastic leukemia (ALL) cells from many patients. We determined whether transgenic expression of CD40L could enhance an antileukemia immune response using a CD40(+) murine lymphoblastic (A20) leukemia and a CD40(-) myeloblastic (WEHI-3) leukemia in a tumor treatment model. Injection of otherwise nonimmunogenic A20 cells in the presence of CD40L induced an immune response active against preexisting A20 tumor at a distant site. Moreover, concomitant local secretion of transgenic interleukin-2 (IL-2) further amplified the antileukemic response induced and increased protection against preexisting tumor. In ex vivo studies, CD40 activation of A20 cells enhances the antigen presenting potential of A20 cells by upregulating expression of B7.1 (CD80), Class I and II MHC molecules, and increases expression of fas antigens. The importance of CD40 activation to the resulting antitumor response is further emphasized by the failure of transgenic CD40L to protect against the CD40(-) WEHI myeloblastic leukemia. Depletion studies showed the protective effects against A20 cells to be mediated by a combination of CD4(+) and CD8(+) T lymphocytes and by natural killer (NK) cells. These results suggest a means by which CD40(+) leukemia cells may be rendered immunogenic in vivo. (C) 1997 by The American Society of Hematology.