Roles and therapeutic potential of CD150high niche-associated regulatory T cells in bone marrow injury and engraftment

CD150高生态位相关调节性T细胞在骨髓损伤和植入中的作用和治疗潜力

• 批准号: 10456272
• 负责人: Joji Fujisaki
• 金额: $ 49.33万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456272
• 关键词: Adenosine; Agonist; Allogenic; Blood; Bone Marrow; Bone Marrow Transplantation; Bone marrow failure; Cells; Clinical; Clonality; Cytoprotection; Development; Engraftment; Exhibits; FOXP3 gene; Failure; Fingerprint; Generations; Genes; Goals; Hematological Disease; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homologous Transplantation; IL7 gene; Immune; Immunocompetent; Immunologics; Immunosuppression; Individual; Injury; Interleukin 7 Receptor; Lead; Location; Lymphocyte; Malignant Neoplasms; Mediating; Metabolic Diseases; Microscopy; Molecular; Molecular Profiling; Mus; Nature; Oxidative Stress; Patients; Pharmacology; Placenta; Population; Purinergic P1 Receptors; Radiation; Radiation Protection; Radiation therapy; Regulatory T-Lymphocyte; Resistance; Role; SLAM protein; Site; Solid; Stem cell transplant; Stress; Surface; T cell clonality; T-Cell Receptor; T-cell receptor repertoire; Testing; Testis; Therapeutic; Tissue Transplantation; Tissues; Translations; Transplantation; clinical translation; conditioning; embryonic stem cell; extracellular; hematopoietic engraftment; hematopoietic stem cell niche; hematopoietic stem cell quiescence; improved; improved outcome; in vivo; insight; irradiation; novel therapeutic intervention; radiation resistance; radioresistant; self-renewal; stem cell biomarkers; stem cell engraftment; stem cell function; stem cell genes; stem cells; transcriptome sequencing; transplantation therapy

Project Abstract Although the stem cell microenvironment, or the niche, has been extensively studied as a site which regulates stem cell functions, immunological attributes of the niche have been largely unexplored. Interestingly, studies conducted over six decades ago revealed that the locations of germline and embryonic stem cells, the testis and placenta, immunological sanctuaries for stem cells, termed immune privileged (IP) sites. In these tissues, transplanted allogeneic or xenogeneic grafts can persist without immune suppressive therapy, distinguishing IP sites from other sites. Little is known about whether tissue-committed stem cell niches serve as IP sites. Our recent studies demonstrated evidence suggesting that the HSC niche within the bone marrow (BM) is an IP site. We showed that unique FoxP3+ regulatory T cells (Tregs) with high expression of an HSC marker, CD150, frequently localized adjacent to HSCs. These Tregs enabled persistence of allo-HSCs in non- conditioned immune competent mice without immune suppression. In non-transplantation settings, niche Tregs protected endogenous HSCs from oxidative stress, maintaining HSC quiescence. These observations suggest that niche Tregs endow HSCs with immune privilege. To promote translation of our findings into clinical settings, we will propose to study roles and therapeutic potential of niche Tregs in hematopoiesis failure following irradiation and in allo-HSC engraftment following non-myeloablative conditioning. We will characterize niche Tregs' stress-resistance, repopulating potential, molecular signatures, and T cell receptor (TCR) repertoire, assessing how these features of niche Tregs contribute to HSC protection or engraftment. Successful studies will identify unprecedented Treg subsets which act as stem cell protectants from immune attack and stress within the niche, decipher mechanisms of this niche Treg-mediated stem cell protection or engraftment, and lead to development of promising therapeutic strategies for post-irradiation BM injury or engraftment by transferring or manipulating niche Tregs. Therefore, the results of our proposed studies will eventually improve outcomes of allo-BM transplantation or radiation therapy for patients with blood disorders, immune deficiency, metabolic diseases, blood malignancies, and solid cancers.

项目摘要 尽管干细胞微环境或小生境作为调节细胞增殖的位点已经被广泛研究， 干细胞的功能，小生境的免疫学属性已经在很大程度上未被探索。有趣的是， 60多年前进行的一项研究显示，生殖系和胚胎干细胞的位置，睾丸， 和胎盘，干细胞的免疫保护区，称为免疫特权（IP）网站。在这些组织中， 移植的同种异体或异种移植物可以在没有免疫抑制治疗的情况下持续存在， 其他网站的网站。很少有人知道是否组织定向干细胞龛作为IP网站。我们 最近的研究表明，有证据表明骨髓（BM）内的HSC生态位是IP 绝佳的价钱我们发现，具有高表达HSC标记物的独特FoxP 3+调节性T细胞（TCFs）， CD 150，经常定位于邻近HSC。这些T细胞能够使非造血干细胞中的allo-HSC持续存在。 无免疫抑制的条件免疫活性小鼠。在非移植环境中， 保护内源性HSC免受氧化应激，维持HSC静止。这些观察结果表明 这个小生境赋予HSC免疫特权。促进我们的发现转化为临床 因此，我们将建议研究小生境T细胞在造血衰竭中的作用和治疗潜力。 照射后和非清髓性预处理后的allo-HSC移植。我们将描述 小生境T细胞的抗逆性、再增殖潜力、分子特征和T细胞受体（TCR） 库，评估这些特征的生态位THBE如何有助于HSC的保护或植入。 成功的研究将确定前所未有的Treg亚群，它们作为干细胞保护剂， 攻击和压力的小生境，破译机制，这个小生境Treg介导的干细胞保护或 移植，并导致有前途的治疗策略的发展，辐射后骨髓损伤或 通过转移或操纵壁龛T细胞来植入。因此，我们建议的研究结果将 最终改善血液病患者的同种异体骨髓移植或放射治疗的结果， 免疫缺陷、代谢疾病、血液恶性肿瘤和实体癌。