Vice President's Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany.
Division of Allergology, Paul-Ehrlich-Institut, Langen, Germany.
Allergy. 2015 Oct;70(10):1259-68. doi: 10.1111/all.12675. Epub 2015 Jul 8.
Monophosphoryl lipid A (MPLA), a nontoxic TLR4 ligand derived from lipopolysaccharide (LPS), is used clinically as an adjuvant in cancer, hepatitis, and malaria vaccines and in allergen-specific immunotherapy. Nevertheless, its cell-activating effects have not been analyzed in a comprehensive direct comparison including a wide range of different immune cells. Therefore, the objective of this study was the side-by-side comparison of the immune-modulating properties of MPLA and LPS on different immune cells.
Immune-activating properties of MPLA and LPS were compared in human monocytes and mast cells (MCs), a mouse endotoxin shock model (ESM), and mouse bone marrow (BM)-derived myeloid dendritic cells (mDCs), T cells (TCs), B cells, and MCs.
In a mouse in vivo ESM and a human ex vivo monocyte activation test (MAT), MPLA induced the same cytokine secretion pattern as LPS (ESM: IL-6, IL-12, TNF-α; MAT: IL-1β, IL-6, TNF-α), albeit at lower levels. Mouse mDCs and ex vivo isolated B cells stimulated with MPLA required a higher threshold to induce TRIF-dependent cytokine secretion (IL-1β, IL-6, IL-10, and TNF-α) than did LPS-stimulated cells. In mDC:DO11.10 CD4 TC cocultures, stimulation with MPLA, but not with LPS, resulted in enhanced OVA-specific IL-4 and IL-5 secretion from DO11.10 CD4 TCs. Unexpectedly, in both human and mouse MCs, MPLA, unlike LPS, did not elicit secretion of pro-inflammatory cytokines.
Compared to LPS, MPLA induced a qualitatively similar, but less potent pro-inflammatory immune response, but was unable to activate human or mouse MCs.
单磷酰脂质 A (MPLA) 是一种源自脂多糖 (LPS) 的无毒 TLR4 配体，临床上用作癌症、肝炎和疟疾疫苗的佐剂以及变应原特异性免疫疗法。然而，其细胞激活作用尚未在包括广泛不同免疫细胞的全面直接比较中进行分析。因此，本研究的目的是并排比较 MPLA 和 LPS 在不同免疫细胞上的免疫调节特性。
在人单核细胞和肥大细胞 (MCs)、小鼠内毒素休克模型 (ESM) 和小鼠骨髓 (BM) 衍生的髓样树突状细胞 (mDCs)、T 细胞 (TCs)、B 细胞和 MCs 中比较 MPLA 和 LPS 的免疫激活特性。
在体内 ESM 和体外单核细胞激活试验 (MAT) 中，MPLA 诱导与 LPS 相同的细胞因子分泌模式（ESM：IL-6、IL-12、TNF-α；MAT：IL-1β、IL-6、TNF-α），尽管水平较低。用 MPLA 刺激的小鼠 mDC 和体外分离的 B 细胞诱导 TRIF 依赖性细胞因子分泌（IL-1β、IL-6、IL-10 和 TNF-α）所需的阈值高于 LPS 刺激的细胞。在 mDC:DO11.10 CD4 TC 共培养物中，用 MPLA 刺激而非 LPS 刺激导致 DO11.10 CD4 TC 中 OVA 特异性 IL-4 和 IL-5 分泌增强。出乎意料的是，在人和小鼠 MC 中，MPLA 不像 LPS 那样引发促炎细胞因子的分泌。
与 LPS 相比，MPLA 诱导了一种定性相似但效力较弱的促炎免疫反应，但不能激活人或鼠 MC。
