Immune privilege of the hematopoieitic stem cell niche

造血干细胞生态位的免疫特权

基本信息

批准号：
9895853
负责人：
Joji Fujisaki
金额：
$ 11.08万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895853
关键词：
Acute Myelocytic Leukemia Adenosine Antibody Therapy Area Biological Assay Bone Marrow Bone Marrow Cells CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CXCL12 gene CXCR4 gene Cell physiology Cells Clinical Data Detection Donor person FOXP3 gene Flow Cytometry Frequencies Generations Goals Graft Rejection Hematopoietic stem cells Home environment Homing Homologous Transplantation ITGAM gene Immune Immune system Immunity Immunocompetent Immunologics Immunosuppression In Vitro Lead Leukemic Cell Ligands MLL-AF9 Maintenance Malignant Neoplasms Mediating Mesenchymal Microscopy Molecular Mus Myeloid Cells Natural Killer Cells Organ Pattern Phenotype Placenta Play Progenitor Cell Engraftment Purinergic P1 Receptors Regulatory T-Lymphocyte Reverse Transcriptase Polymerase Chain Reaction Role Site Stem cell transplant Stromal Cell-Derived Factor 1 Testing Testis Tissues Transplantation base cancer stem cell chemokine chemokine receptor extracellular in vivo inhibitor/antagonist insight leukemia leukemic stem cell novel novel therapeutics prevent recruit residence stem cell niche stem cells

项目摘要

Project Abstract Although the stem cell niche has been extensively studied as a site that regulates stem cell functions, immunological attributes of the niche have remained largely unexplored. Interestingly, the testis and the placenta, organs for residence of stem cells, are known to be immunological sanctuaries for stem cells, termed immune privileged (IP) sites. Rigorous immune suppression in IP sites is evidenced by survival of transplanted allogeneic or xenogeneic grafts without any exogenous immune suppressive therapy. Little is known about whether tissue-committed stem cell niches are IP sites, like the testis and the placenta. The overall hypothesis is that one of the best-characterized stem cell niches, the hematopoietic stem and progenitor cell (HSPC) niche in the bone marrow (BM), is an IP site. IP in the niche may prevent rejection of transplanted allogeneic (allo-) HSPCs, and shield malignant stem cells from immune attack. Therefore, IP may be a novel principle that provides a mechanistic underpinning of several clinical settings. Our previous study indicates that the HSPC niche is an IP site. Highly sensitive in vivo microscopy (IVM) enabled detection of allo-HSPCs persisting in immune competent mice without immune suppressive therapy for more than 60 days. Moreover, FoxP3+ regulatory T cells (Tregs) frequently formed clusters with HSPCs. Systemic Treg depletion led to allo-HSPC rejection. The data suggest that Tregs endow the niche with IP. We further observed that MLL-AF9 leukemia stem cells (LSCs) home to BM Tregs, a hallmark of IP sites, suggesting that IP shields LSCs. To develop a new therapy to manipulate IP to promote allo-HSPC engraftment or eradicate BM malignancies, it is important to obtain further mechanistic insights into IP. In Aim 1, we will investigate the role of BM Tregs, mesenchymal cells, and CD11b+Gr1+ myeloid cells in IP maintenance and allo-HSPC persistence without immune suppression. To achieve this goal, we will employ the following four approaches: a) inhibition of Treg homing to the BM due to conditional deletion of CXCR4 in Tregs; b) conditional deletion of CD39 in Tregs; c) conditional deletion of CXCL12 in lepr+ mesenchymal cells; and d) CD11b+Gr1+ cell depletion by anti-Gr1 antibody treatment. We will determine whether these approaches lead to rejection of allo-HSPCs transplanted without immune suppression, by using in vivo microscopy, flow cytometry, and secondary transplantation assay. In Aim 2, we will test whether IP shields LSCs from immunity, and further elucidate the role of BM Tregs, mesenchymal cells, and CD11b+Gr1+ myeloid cells in allowing LSCs to evade immunity. We will determine whether rejection of MLL-AF9 leukemia is induced by a) lack of BM Tregs due to CXCR4 deletion in Tregs, b) CD39 inhibitor treatment, c) CXCL12 deletion in lepr+ mesenchymal cells, and d) myeloid cell depletion. Successful studies will create a novel paradigm that the HSPC niche is an immunological sanctuary for both allo-HSPCs and malignant stem cells. Furthermore, these mechanistic and systematic analyses of IP will establish novel therapeutic strategies for allo-HSPC transplantation and malignancies.

项目摘要尽管干细胞生态位作为调节干细胞功能的位点已被广泛研究，该生态位的免疫学属性在很大程度上仍未被探索。有趣的是，睾丸和胎盘是干细胞居住的器官，已知是干细胞的免疫避难所，称为免疫特权 (IP) 站点。移植物的存活证明了 IP 位点的严格免疫抑制同种异体或异种移植物，无需任何外源性免疫抑制治疗。鲜为人知的是组织定型干细胞巢是否是 IP 位点，如睾丸和胎盘。总体假设造血干细胞和祖细胞 (HSPC) 生态位是最具特征的干细胞生态位之一在骨髓（BM）中，是一个IP位点。利基中的 IP 可以防止移植同种异体 (allo-) 的排斥 HSPC，并保护恶性干细胞免受免疫攻击。因此，知识产权可能是一项新颖的原则，为多种临床环境提供了机械基础。我们之前的研究表明 HSPC 利基市场是一个 IP 网站。高灵敏体内显微镜 (IVM) 能够检测持续存在的异基因 HSPC 免疫能力强的小鼠未接受免疫抑制治疗超过 60 天。此外，FoxP3+ 调节性 T 细胞 (Treg) 经常与 HSPC 形成簇。系统性 Treg 耗竭导致异基因 HSPC 拒绝。数据表明 Tregs 赋予了利基市场 IP。我们进一步观察到 MLL-AF9 白血病干细胞 (LSC) 是 BM Tregs 的所在地，这是 IP 站点的标志，表明 IP 屏蔽了 LSC。开发一个操纵 IP 促进异基因 HSPC 植入或根除 BM 恶性肿瘤的新疗法非常重要获得对知识产权的进一步机制见解。在目标 1 中，我们将研究 BM Tregs、间充质细胞和 CD11b+Gr1+ 骨髓细胞在 IP 维持和异基因 HSPC 持续性中无需免疫抑制。为了实现这一目标，我们将采用以下四种方法：a）抑制Treg归巢由于Tregs中有条件删除CXCR4而导致BM； b) 有条件地删除Tregs中的CD39； c) 有条件的 lepr+间充质细胞中CXCL12的缺失； d) 抗 Gr1 抗体消除 CD11b+Gr1+ 细胞治疗。我们将确定这些方法是否会导致未经移植的同种异体 HSPC 的排斥通过使用体内显微镜、流式细胞术和二次移植测定来抑制免疫抑制。在目标2，我们将测试IP是否屏蔽LSCs免受免疫，并进一步阐明BM Tregs的作用，间充质细胞和 CD11b+Gr1+ 骨髓细胞使 LSC 逃避免疫。我们将确定 MLL-AF9 白血病的排斥是否是由 a) 由于 Tregs 中 CXCR4 缺失而导致 BM Tregs 缺乏引起的，b) CD39 抑制剂治疗，c) lepr+ 间充质细胞中的 CXCL12 缺失，以及 d) 骨髓细胞耗竭。成功的研究将创造一个新的范式，即 HSPC 生态位是两者的免疫避难所同种异体 HSPC 和恶性干细胞。此外，这些对知识产权的机械和系统分析将建立异基因 HSPC 移植和恶性肿瘤的新治疗策略。