Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation
Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation
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DOI：
10.1186/1479-5876-7-93
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发表时间：
2009-11-11
影响因子：
7.4
通讯作者：
Vonderheide, Robert H.
中科院分区：
文献类型：
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作者：
Carpenter, Erica L.;Mick, Rosemarie;Vonderheide, Robert H.
背景：CD40活化抗原呈递细胞（APC）如树突状细胞（DC）和B细胞在T细胞免疫的免疫许可中起重要作用。激动剂CD40抗体先前已在小鼠模型中显示可激活APC并增强肿瘤免疫；在人体内，cd40激活的DC细胞和B细胞在体外诱导肿瘤特异性T细胞。尽管由于缺乏合适和可用的药物，这些发现在癌症患者的临床转化以前受到限制，但激动剂CD40单克隆抗体CP-870,893的I期研究正在出现有希望的临床结果。CP-870,893输注最突出的药效学作用是外周B细胞调节，但cp870,893介导的B细胞活化和对T细胞反应性的潜在影响的直接证据尚未报道，尽管越来越多的证据表明B细胞，如DC，调节细胞免疫。方法：体外用CP-870,893刺激纯化的外周血总CD19+ B细胞、CD19+ CD27+记忆细胞或CD19+ CD27（阴性）亚群，无论是否存在toll样受体9 （TLR9）配体CpG寡脱氧核苷酸（ODN）。流式细胞术检测B细胞表面分子表达及细胞因子分泌情况。活化的B细胞被用作混合淋巴细胞反应的刺激物，以评估其诱导同种异体T细胞反应的能力。结果：与CP-870,893激活的B细胞（包括记忆B细胞和初始B细胞）孵育，CD86, CD70， CD40和MHC I类和II类上调。cp -870,893活化的B细胞诱导T细胞增殖和T细胞分泌包括ifn - γ和IL-2在内的效应细胞因子。通过与临床级试剂序列相同的CpG ODN共同刺激TLR9可增加这些作用。结论：CD40 mAb CP-870,893可激活记忆和初始B细胞，并触发它们的T细胞刺激能力。同时TLR9结扎增强了单独使用CP-870,893的效果。这些结果为利用现有的临床试剂将CD40和TLR9联合激活用于新型肿瘤免疫治疗策略提供了进一步的理论依据。
Background: CD40 activation of antigen presenting cells (APC) such as dendritic cells (DC) and B cells plays an important role in immunological licensing of T cell immunity. Agonist CD40 antibodies have been previously shown in murine models to activate APC and enhance tumor immunity; in humans, CD40-activated DC and B cells induce tumor-specific T cells in vitro. Although clinical translation of these findings for patients with cancer has been previously limited due to the lack of a suitable and available drug, promising clinical results are now emerging from phase I studies of the agonist CD40 monoclonal antibody CP-870,893. The most prominent pharmacodynamic effect of CP-870,893 infusion is peripheral B cell modulation, but direct evidence of CP870,893-mediated B cell activation and the potential impact on T cell reactivity has not been reported, despite increasing evidence that B cells, like DC, regulate cellular immunity.Methods: Purified total CD19+ B cells, CD19+ CD27+ memory, or CD19+ CD27(neg) subsets from peripheral blood were stimulated in vitro with CP-870,893, in the presence or absence of the toll like receptor 9 (TLR9) ligand CpG oligodeoxynucleotide (ODN). B cell surface molecule expression and cytokine secretion were evaluated using flow cytometry. Activated B cells were used as stimulators in mixed lymphocyte reactions to evaluate their ability to induce allogeneic T cell responses.Results: Incubation with CP-870,893 activated B cells, including both memory and naive B cells, as demonstrated by upregulation of CD86, CD70, CD40, and MHC class I and II. CP-870,893-activated B cells induced T cell proliferation and T cell secretion of effector cytokines including IFN-gamma and IL-2. These effects were increased by TLR9 co-stimulation via a CpG ODN identical in sequence to a well-studied clinical grade reagent.Conclusion: The CD40 mAb CP-870,893 activates both memory and naive B cells and triggers their T cell stimulatory capacity. Simultaneous TLR9 ligation augments the effect of CP-870,893 alone. These results provide further rationale for combining CD40 and TLR9 activation using available clinical reagents in strategies of novel tumor immunotherapy.