异常T细胞在真性红细胞胞增多症发病中的作用机制研究

Polycythemia vera (PV) is a representative disease model of myeloproliferative neoplasms. The occurance and development of PV involved a complicated physiopathologic process, which not only include genetic and epigenetic mutation, but also related to the immunological regulation of aberrant hematological stem and progenitor cells (HSPC). Experimental investigation show that T cell from PV patient is abnormal, which led to robust engraftment in the NOD/SCID mice, and the conditional medium from these cells contribute to endogenous erythroid colony formation of CD34 posive cells from PV patients. Based on the previous work and the translational resouces from our hospital, our group will start a collaborative work with Pr Xu M to clarifiy the phenotype of T cells in the pathogenesis of PV, the functional characteristics, and the molecular and cellular basis. Interferon alpha (IFNα) will be recuited as a tool to explore the effects of inhibiting abnormal T cells to HSPC of PV patients, expecially to the progress of PV to PPMF. Furthermore, the study of abormal T cells in PV will provide a theoretical basis of multiple target therapy in PV patients.

以真性红细胞增多症（PV）为代表的骨髓增殖性肿瘤的发生和进展是一个复杂的病理生理过程，除了遗传学和表观遗传学异常，对造血干/祖细胞恶性克隆微环境的免疫调控也与疾病进程关系密切。PV的T细胞存在异常，能在NOD/SCID小鼠中成功移植，而且其条件培养液能够促进PV患者CD34阳性细胞的内源性红系集落形成。本课题组与许明江教授合作，以此为基础结合临床实际问题，明确在PV发病及进展中异常T细胞的表型特征；阐明异常T细胞的功能特点；并探讨其内在的细胞生物学和分子生物学机制。同时，应用临床对PV治疗有效的干扰素（IFNα）为工具，验证通过抑制异常T细胞对PV造血干/祖细胞恶性克隆的作用，尤其是对PPMF等疾病进展的影响。总之，本研究在造血微环境的免疫调控层面，阐明异常T细胞在PV发病和疾病进展中的重要性，为多靶点治疗PV提供理论依据。

真性红细胞增多症(PV)是费城染色体阴性骨髓增殖性肿瘤（myeloproliferative neoplasms，MPN）的主要代表，其发生和进展是一个复杂的病理生理过程。除了遗传学和表观遗传学异常，包含T细胞在内的造血微环境调控也与疾病进程关系密切。本研究首先分析了我国PV患者生存现状和不良预后的危险因素；阐明了PV 患者T细胞增殖能力及T细胞亚群变化特征；分析了PV患者T细胞在NOD/SCID小鼠体内植入及分化能力；发现PV患者T细胞分泌GM-CSF以及IL-11水平较正常人明显增高；分析了干扰素（IFNα）等治疗药物对PV疾病进展及造血微环境的作用，发现IFNα的治疗可以减缓post-PV MF发生。建立造血干细胞体外向T淋巴细胞分化体系以及PV患者外周血来源的iPSC，为进一步研究T细胞在PV发病中的作用提供了重要工具。本研究的实施为多靶点治疗PV提供了重要的实验依据。