Systems-level analysis of therapeutic helminth-induced immune modulation in patients with rheumatoid arthritis

在卫生学假说的基础上，通过故意感染猪旋毛虫(Trichuris suis ova，TSO)治疗类风湿关节炎(RA)有望改善疾病，与目前批准的治疗方法相比，副作用更少。通过诱导机体自身特定的免疫调节途径，而不是传统药物对免疫系统的外在抑制，使这种新的治疗理念特别适合于治疗慢性炎症性疾病，如RA，需要终生服药和对治疗的耐受性。为了深入了解TSO治疗的作用机制，并为精确医学治疗RA做出贡献，研究TSO治疗过程中免疫特征的变化及其与疾病活动性、治疗反应和血清致病抗体或炎性细胞因子水平等临床参数的关系是非常有意义的。在本方案中，在一项双盲、安慰剂对照的临床先导试验中，40维单细胞质量细胞术(CyTOF)将用于系统地研究接受靶向和及时控制的TSO治疗的RA患者血液免疫细胞的组成和激活状态。我们高度尖端的细胞学方法与临床和血清学数据相结合，将对白细胞的表型、功能和TSO治疗反应提供前所未有的详细见解。已建立的非监督计算数据分析将用于提取i)RA、ii)免疫系统对蠕虫感染的反应以及iii)临床参数(如疾病活动性或未来治疗成功)的免疫特征。这项研究将首次从系统水平深入了解类风湿关节炎患者的血液免疫细胞失调，并揭示TSO治疗对类风湿相关免疫细胞异常的影响。总之，我们希望我们的项目能够阐明蠕虫疗法在人类中的作用机制，并为慢性炎症性疾病的精确医学思想做出贡献。

Based on the hygiene hypothesis, the treatment of rheumatoid arthritis (RA) by intentional helminth infection with Trichuris suis ova (TSO) promises amelioration of the disease associated with less side effects as compared to currently approved therapies. The induction of the bodys own specific immunomodulatory pathways rather than the extrinsic suppression of the immune system by conventional medication, makes this new treatment concept particularly suitable for treatment of chronic inflammatory diseases such as RA, which require life-long medication and toleration of therapy.In order to gain insight in the mechanism of action of TSO therapy and to contribute to precision medicine in the treatment of RA, it is of great interest to study how immune features change during the response to TSO therapy, and how this relates to clinical parameters such as disease activity, response to therapy and serum levels of pathogenic antibodies or inflammatory cytokines.In this proposal, 40-dimensional single-cell mass cytometry (CyTOF) will be used to systematically study the composition and activation state of blood immune cells from RA patients undergoing targeted and timely controlled TSO treatment in a double-blinded, placebo-controlled clinical pilot trial. Our highly cutting-edge cytometric approach combined with clinical and serological data will give unprecedentedly detailed insights into the phenotype, functionality and TSO treatment response of white blood cells. Established unsupervised computational data analyses will be used to extract immune signatures of i) RA, ii) the immune systems response to helminth infection, and iii) clinical parameters such as disease activity or future therapy success. This study will, for the first time, provide systems-level insights into blood immune cell dysregulation in RA patients, and reveal the impact of TSO treatment on RA-associated immune cell abnormalities. Altogether, we expect our project to elucidate mechanism of action of helminth therapy in humans and contribute to the idea of precision medicine in chronic inflammatory diseases.