树突状细胞（DC）培养中的免疫原诱导因素（PINDs）导致 DC 刺激的 T 细胞抗白血病功能受损。

Paramunity-inducing Factors (PINDs) in dendritic cell (DC) cultures lead to impaired antileukemic functionality of DC-stimulated T-cells.

机构信息

Dept for Hematopoetic Transplantations, MED3, University of Munich, Germany.

VironPearl Biotech GmbH, Munich, Germany.

出版信息

Cell Immunol. 2018 Jun;328:33-48. doi: 10.1016/j.cellimm.2018.03.005. Epub 2018 Mar 16.

DOI:10.1016/j.cellimm.2018.03.005

PMID:29580554

Abstract

INTRODUCTION

Paramunity-inducing-Factors (PINDs) consist of attenuated/inactivated viruses of various poxvirus-genera, used in veterinary medicine as non-antigen-specific, non-immunising stimulators of the innate immune system against infectious and malignant diseases. Their danger-signaling-interactions were tested for their capacity to improve leukemic antigen-presentation on DC generated from AML-patients' blasts ('DC') and DC-stimulation/activation of antileukemic T-cells.

METHODS

We analyzed, whether the addition of PINDs during DC cultures (15 healthy, 22 leukemic donors) and mixed lymphocyte culture (MLC, n = 15) with autologous (n = 6), allogeneic (n = 2) or T-cells after stem cell transplantation (SCT; n = 7) would alter the quality and quantity of DC, the composition of T-cell-subsets, and/or their antileukemic functionality (AF) as studied by FACS and functional Fluorolysis-cytotoxicity-assays.

RESULTS

Effects on 1. DC-cultures: PINDs in DC-cultures lead to increased proportions of mature DC and DC, but reduced proportions of viable and overall, as well as TLR4- and TLR9-expressing DC. 2. MLC: PINDs increased early (CD8+) T-cell activation (CD69+), but reduced proportions of effector-T-cells after MLC 3. AF: Presence of PINDs in DC- and MLC-cultures reduced T-cells' as well as innate cells' antileukemic functionality. 4. Cytokine-release profile: Supernatants from PIND-treated DC- and MLC-cultures resembled an inhibitory microenvironment, correlating with impaired blast lysis.

CONCLUSIONS

Our data shows that addition of PINDs to DC-cultures and MLC result in a "blast-protective-capacity" leading to impaired AF, likely due to changes in the composition of T-/innate effector cells and the induction of an inhibitory microenvironment. PINDs might be promising in treating infectious diseases, but cannot be recommended for the treatment of AML-patients due to their inhibitory influence on antileukemic functionality.

摘要

简介

免疫原性诱导因子（PINDs）由各种痘病毒属的减毒/灭活病毒组成，在兽医医学中作为非抗原特异性、非免疫刺激物，用于刺激针对传染病和恶性疾病的固有免疫系统。测试了它们的危险信号相互作用，以评估其改善急性髓细胞白血病（AML）患者的原始细胞生成的树突状细胞（DC）上白血病抗原呈递的能力，以及对白血病 T 细胞的 DC 刺激/激活作用。

方法

我们分析了在 DC 培养过程中（15 名健康供体，22 名白血病供体）和混合淋巴细胞培养（MLC，n=15）中添加 PINDs 是否会改变 DC 的质量和数量、T 细胞亚群的组成，以及它们的抗白血病功能（AF），研究方法是通过流式细胞术和功能荧光溶解细胞毒性测定。

结果

DC 培养物的影响：PINDs 在 DC 培养物中导致成熟 DC 和 DC 的比例增加，但活细胞和总细胞的比例以及 TLR4 和 TLR9 表达的 DC 比例降低。2. MLC：PINDs 增加了早期（CD8+）T 细胞的激活（CD69+），但减少了 MLC 后效应 T 细胞的比例。3. AF：在 DC 和 MLC 培养物中存在 PINDs 会降低 T 细胞和先天细胞的抗白血病功能。4. 细胞因子释放谱：来自 PIND 处理的 DC 和 MLC 培养物的上清液类似于抑制性微环境，与抑制性微环境相关联，与破坏原始细胞的能力受损相关联。