Lin Zhi, Huang Ying, Jiang Hua, Zhang Di, Yang Yanwei, Geng Xingchao, Li Bo
National Institute for Food and Drug Control, National Center for Safety Evaluation of Drugs, Beijing Key Lab for Preclinical Safety Evaluation of Drugs, Beijing, China.
Ann Transl Med. 2021 Feb;9(3):257. doi: 10.21037/atm-20-4548.
The monkey is a primary species used in toxicological research. However, the failures of preclinical studies to predict a life-threatening "cytokine storm", which, for instance, rapidly occurred in six healthy volunteers with the CD28 superagonist monoclonal antibody (mAb) TGN1412 in the first-in-human phase I clinical trial, have emphasized a need to clarify the differences between human and monkey immune systems.
In the present study, we analyzed and compared the lymphocyte proliferation, cytokine secretion, and gene expression profiles after phytohemagglutinin (PHA) and lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells (PBMCs) from three healthy humans and cynomolgus monkeys ().
The results derived from comparison with the corresponding control groups showed that PHA in humans induced a stronger proliferation and wider range of cytokine secretion, along with a greater number of differently expressed genes (DEGs), than when PHA was applied in cynomolgus monkeys. The significant upregulation of genes involved in the mitotic cell cycle, including , , , and , was observed in human PBMCs with PHA stimulation, while only infrequent or slight upregulation occurred in cynomolgus monkey PBMCs, which may be one of the reasons for a stronger response to PHA in humans. In contrast to PHA, LPS in both species induced a similar proliferation ratio, cytokine profile, and DEG count, suggesting that human and cynomolgus monkeys have a similar response intensity for innate immune responses. Furthermore, 38 and 20 overlapped genes under PHA and LPS stimulation, respectively, were found in both species. These overlapped DEGs were associated with the same biological functions, including DNA replication, mitosis, immune response, chemotaxis, and inflammatory response. Thus, these results might reflect the highly conserved signatures of immune responses to PHA/LPS stimulation across the primates. Moreover, there were some differences in antigen processing and presentation, and the interferon gamma (INF-γ)-mediated signaling pathway in these species detected by gene expression profile study.
In conclusion, this is the first study to compare data on the responses of PBMCs to PHA and LPS in humans versus cynomolgus monkeys, and these findings may provide crucial insights into translating non-human primate (NHP) studies into human trials.
猴子是毒理学研究中使用的主要物种。然而，临床前研究未能预测出危及生命的“细胞因子风暴”，例如，在首次人体I期临床试验中，6名健康志愿者使用CD28超激动剂单克隆抗体（mAb）TGN1412后迅速发生了这种情况，这凸显了阐明人类和猴子免疫系统差异的必要性。
在本研究中，我们分析并比较了来自三名健康人类和食蟹猴的外周血单个核细胞（PBMC）在植物血凝素（PHA）和脂多糖（LPS）刺激后的淋巴细胞增殖、细胞因子分泌和基因表达谱。
与相应对照组比较的结果表明，与对食蟹猴应用PHA相比，PHA在人类中诱导了更强的增殖和更广泛的细胞因子分泌，以及更多数量的差异表达基因（DEG）。在PHA刺激的人类PBMC中观察到参与有丝分裂细胞周期的基因（包括[具体基因名称未给出]、[具体基因名称未给出]、[具体基因名称未给出]和[具体基因名称未给出]）显著上调，而在食蟹猴PBMC中仅偶尔或轻微上调，这可能是人类对PHA反应更强的原因之一。与PHA相反，两种物种中的LPS诱导了相似的增殖率、细胞因子谱和DEG数量，表明人类和食蟹猴对先天免疫反应具有相似的反应强度。此外，在两种物种中分别发现了在PHA和LPS刺激下38个和20个重叠基因。这些重叠的DEG与相同的生物学功能相关，包括DNA复制、有丝分裂、免疫反应、趋化性和炎症反应。因此，这些结果可能反映了灵长类动物对PHA/LPS刺激的免疫反应的高度保守特征。此外，通过基因表达谱研究检测到这些物种在抗原加工和呈递以及干扰素γ（INF-γ）介导的信号通路方面存在一些差异。
总之，这是第一项比较人类和食蟹猴PBMC对PHA和LPS反应数据的研究，这些发现可能为将非人灵长类动物（NHP）研究转化为人体试验提供关键见解。
