PDF(Pubmed)
Abstract：
UNASSIGNED: Therapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit cytotoxic responses against malignant B cells. However, efficacy is often compromised due to a suppressive microenvironment that interferes with cellular immune responses. To overcome this suppression, agonists of pattern recognition receptors have been studied which promote direct cytotoxicity or elicit anti-tumoral immune responses. NOD2 is an intracellular pattern recognition receptor that participates in the detection of peptidoglycan, a key component of bacterial cell walls. This detection then mediates the activation of multiple signaling pathways in myeloid cells. Although several NOD2 agonists are being used worldwide, the potential benefit of these agents in the context of antibody therapy has not been explored.
UNASSIGNED: Primary cells from healthy-donor volunteers (PBMCs, monocytes) or CLL patients (monocytes) were treated with versus without the NOD2 agonist L18-MDP, then antibody-mediated responses were assessed. In vivo, the Eµ-TCL1 mouse model of CLL was used to test the effects of L18-MDP treatment alone and in combination with anti-CD20 antibody.
UNASSIGNED: Treatment of peripheral blood mononuclear cells with L18-MDP led to activation of monocytes from both healthy donors and CLL patients. In addition, there was an upregulation of activating FcγR in monocytes and a subsequent increase in antibody-mediated phagocytosis. This effect required the NF-κB and p38 signaling pathways. Treatment with L18-MDP plus anti-CD20 antibody in the Eµ-TCL model of CLL led to a significant reduction of CLL load, as well as to phenotypic changes in splenic monocytes and macrophages.
UNASSIGNED: Taken together, these results suggest that NOD2 agonists help overturn the suppression of myeloid cells, and may improve the efficacy of antibody therapy for CLL.
UNASSIGNED: Primary cells from healthy-donor volunteers (PBMCs, monocytes) or CLL patients (monocytes) were treated with versus without the NOD2 agonist L18-MDP, then antibody-mediated responses were assessed. In vivo, the Eµ-TCL1 mouse model of CLL was used to test the effects of L18-MDP treatment alone and in combination with anti-CD20 antibody.
UNASSIGNED: Treatment of peripheral blood mononuclear cells with L18-MDP led to activation of monocytes from both healthy donors and CLL patients. In addition, there was an upregulation of activating FcγR in monocytes and a subsequent increase in antibody-mediated phagocytosis. This effect required the NF-κB and p38 signaling pathways. Treatment with L18-MDP plus anti-CD20 antibody in the Eµ-TCL model of CLL led to a significant reduction of CLL load, as well as to phenotypic changes in splenic monocytes and macrophages.
UNASSIGNED: Taken together, these results suggest that NOD2 agonists help overturn the suppression of myeloid cells, and may improve the efficacy of antibody therapy for CLL.
摘要：
■治疗性抗体已成为治疗肿瘤疾病的主要策略。对于慢性淋巴细胞白血病，针对CD20的抗体用于靶向并引发针对恶性B细胞的细胞毒性反应。然而,由于干扰细胞免疫反应的抑制性微环境，功效通常会受到损害。为了克服这种抑制，已经研究了模式识别受体的激动剂,其促进直接的细胞毒性或引发抗肿瘤免疫应答。NOD2是一种细胞内模式识别受体，参与肽聚糖的检测，细菌细胞壁的关键组成部分。这种检测然后介导骨髓细胞中多种信号传导途径的激活。尽管几种NOD2激动剂正在全球范围内使用，这些药物在抗体治疗中的潜在益处尚未被研究.
■来自健康供体志愿者的原代细胞（PBMC，单核细胞）或CLL患者（单核细胞）用NOD2激动剂L18-MDP治疗，然后评估抗体介导的反应。在体内,我们使用CLL的Eµ-TCL1小鼠模型测试L18-MDP单独治疗和联合抗CD20抗体治疗的效果.
■用L18-MDP处理外周血单核细胞导致来自健康供体和CLL患者的单核细胞活化。此外,单核细胞中激活FcγR上调,随后抗体介导的吞噬作用增加.这种效应需要NF-κB和p38信号通路。在CLL的Eµ-TCL模型中，用L18-MDP加抗CD20抗体治疗导致CLL负荷显着降低，以及脾单核细胞和巨噬细胞的表型变化。
■放在一起，这些结果表明，NOD2激动剂有助于推翻对骨髓细胞的抑制，并可能提高CLL抗体治疗的疗效。
■来自健康供体志愿者的原代细胞（PBMC，单核细胞）或CLL患者（单核细胞）用NOD2激动剂L18-MDP治疗，然后评估抗体介导的反应。在体内,我们使用CLL的Eµ-TCL1小鼠模型测试L18-MDP单独治疗和联合抗CD20抗体治疗的效果.
■用L18-MDP处理外周血单核细胞导致来自健康供体和CLL患者的单核细胞活化。此外,单核细胞中激活FcγR上调,随后抗体介导的吞噬作用增加.这种效应需要NF-κB和p38信号通路。在CLL的Eµ-TCL模型中，用L18-MDP加抗CD20抗体治疗导致CLL负荷显着降低，以及脾单核细胞和巨噬细胞的表型变化。
■放在一起，这些结果表明，NOD2激动剂有助于推翻对骨髓细胞的抑制，并可能提高CLL抗体治疗的疗效。
