Plasmacytoid Dendritic Cell microRNAS in Transplantation

浆细胞样树突状细胞 microRNAS 在移植中的应用

• 批准号: 9302655
• 负责人: Sheri M. Krams
• 金额: $ 20.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-22 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302655
• 关键词: Adoptive Transfer; Allografting; Antigens; Biological; Biological Process; Bone Marrow; Cells; Clinic; Data; Dendritic Cells; Development; Family; Generations; Goals; Graft Survival; Heart; Heart Transplantation; Hepatic; ITGAM gene; Immune; Immune response; Immune system; Immunosuppressive Agents; Injection of therapeutic agent; Kidney; Kidney Transplantation; Liver; Lymphoid Tissue; Mediating; Messenger RNA; MicroRNAs; Molecular; Mus; Organ Transplantation; Outcome; Pancreas; Play; Property; Quality of life; Role; Small Intestines; Solid; Technology; Testing; Therapeutic; Transcript; Translations; Transplant Recipients; Transplantation; base; heart allograft; high risk; improved; improved outcome; in vivo; liver allograft; member; novel; overexpression

7. Project Summary Liver allografts are generally well tolerated, and other solid organ allografts, such as the small intestine, heart, and kidney, transplanted concurrently with livers show improved graft outcomes. However, the mechanisms underlying “hepatic tolerance” have yet to be elucidated. Hepatic plasmacytoid dendritic cells p(DC) have been shown to have diminished ability to stimulate an immune response as compared with DC in lymphoid tissue. Further, functional differences between DC subsets, including (p)DC and conventional (c)DC, have been defined, with the hypothesis that immature pDC inherently dampen an immune response and are tolerogenic. Indeed, multiple studies show that pDC play a unique and important role in the generation of tolerance. However, the mechanism responsible for the tolerogenic properties of pDC remains elusive. Recently we determined that six members of the miR-181 family of microRNAs were all significantly increased in hepatic pDC as compared to hepatic cDC. Further we show that hepatic pDC significantly prolong solid organ allograft survival and this enhanced survival in abrogated in the absence of miR-181a. The overall goals of our proposal are: 1) to determine the mechanism by which miR-181-expressing pDC alters the immune system to improve the survival of solid organ allografts and 2) exploiting the graft prolonging capacity of miR-181-expressing pDC to generate a therapeutic to prolong allograft survival. In our first specific aim, we will test the hypothesis that miR-181-expressing pDC modifies the immune response towards enhanced graft survival. A complete profiling of the immune response after transplantation with miR-181+ and miR-181-/- pDC, using cutting-edge CyTOF technology, will be performed. The mRNA target of miR-181-expressing pDC, and biological function, will be determined. Further, it will be determined if miR-181-expressing pDC prolongs allograft survival by functioning in cis or trans. In our second specific aim we will test the hypothesis that (over)expression of miR-181a can prolong allograft survival. Since pDC are present in such limited numbers development of hepatic pDC as a cellular therapeutic is limited. In this Aim we will examine whether over-expression of miR-181 in the more plentiful bone marrow derived DC can prolong graft survival. Results from these highly novel studies will result in improved outcomes, and enhance the quality of life for transplant recipients, and their families.

七、项目概要 同种异体肝脏移植通常具有良好的耐受性，而其他实体器官同种异体移植，例如小肠、心脏、 与肝脏同时移植的肾脏和肾脏显示出移植结果的改善，但其机制尚不清楚。 潜在的“肝耐受”尚未阐明 肝浆细胞样树突状细胞 p(DC) 尚未阐明。 与淋巴组织中的 DC 相比，其刺激免疫反应的能力减弱。 此外，DC 子集（包括 (p)DC 和常规 (c)DC）之间的功能差异已被 定义，假设未成熟的 pDC 本质上会抑制免疫反应并且具有耐受性。 事实上，多项研究表明 pDC 在耐受性的产生中发挥着独特而重要的作用。 然而，最近我们对 pDC 的耐受性的机制仍不清楚。 确定 miR-181 microRNA 家族的 6 个成员在肝脏中均显着增加 pDC 与肝 cDC 相比，我们进一步表明肝 pDC 显着延长实体器官同种异体移植的时间。 存活率以及在缺乏 miR-181a 的情况下这种存活率的提高是我们提案的总体目标。 是：1）确定表达 miR-181 的 pDC 改变免疫系统以改善的机制 实体器官同种异体移植物的存活和 2) 利用表达 miR-181 的 pDC 的移植物延长能力 产生延长同种异体移植物存活的治疗方法在我们的第一个具体目标中，我们将检验该假设。 表达 miR-181 的 pDC 可以改变免疫反应，从而增强移植物的存活率 A。 使用 miR-181+ 和 miR-181-/- pDC 移植后完整分析免疫反应 尖端的 CyTOF 技术，将进行表达 miR-181 的 pDC 的 mRNA 靶标。 此外，将确定表达miR-181的pDC是否延长。 通过顺式或反式功能实现同种异体移植存活 在我们的第二个具体目标中，我们将检验以下假设： miR-181a 的（过度）表达可以延长同种异体移植物的存活时间，因为 pDC 存在于如此有限的细胞中。 肝 pDC 作为细胞治疗药物的开发数量是否有限。 在更多的骨髓来源的 DC 中过度表达 miR-181 可以延长移植物的存活率。 这些高度新颖的研究将改善结果，并提高移植的生活质量 受助者及其家人。