In Utero Tolerance Induction

描述(由申请人提供)： 这项为期五年的计划的目标是使首席研究人员能够在通过使用宫内造血细胞移植诱导耐受的临床相关大动物模型中获得新的技能和经验。这将建立在艾伦·弗莱克博士实验室获得的小鼠模型的先前经验基础上，并补充儿科外科、实体器官移植和胎儿治疗方面的临床培训。这种独特的专业知识组合有望转化为一种临床相关的方法，用于治疗产前诊断的疾病，一旦在子宫内建立了供者特异性耐受，出生后可以通过造血或实体器官移植进行治疗。大卫·萨克斯博士将在整个研究计划中指导首席研究员。萨克斯博士是马萨诸塞州总医院移植生物学研究中心(TBRC)的主任，也是耐受性和造血嵌合体研究领域备受尊敬的领导者。他作为导师的良好记录，现在包括几个久负盛名的独立外科调查人员。与包括艾伦·弗莱克博士和梅根·赛克斯博士在内的顾问小组一起，萨克斯博士将提供一个丰富的环境，让首席研究人员可以发展成为独立研究人员。 该研究计划将建立在萨克斯博士的实验室在过去20年里开发的嵌合体和肾移植耐受的成熟微型猪模型的基础上。目标是确定和优化在小型猪的子宫内造血细胞移植后实现嵌合体和肾移植耐受所需的参数。其具体目的是：1)比较骨髓和细胞因子动员的外周血单个核细胞(CM-PBMC)作为供体细胞来源以实现稳定的多系植入；2)确定作为供体细胞来源的母系和父系造血细胞来源是否存在差异；3)确定嵌合体与出生后对供者特异性肾移植的耐受性之间的关系。这将是首次尝试在基因定义明确的大动物模型中系统分析可能对宫内造血细胞移植最终临床成功至关重要的因素。

DESCRIPTION (provided by applicant): The objective of this five-year proposal is to allow the principal investigator to acquire new skills and experience in a clinically relevant large animal model of tolerance induction through the use of in utero hematopoietic cell transplantation. This will build on prior experience in the murine model obtained in the laboratory of Dr. Alan Flake and complement clinical training in pediatric surgery, solid organ transplantation, and fetal therapy. This unique combination of expertise will hopefully translate into a clinically relevant approach to the treatment of prenatally diagnosed conditions that can be treated with either hematopoietic or solid organ transplantation after birth, once donor specific tolerance has been established in utero. Dr. David Sachs will mentor the principal investigator throughout the research program. Dr. Sachs is Director of the Transplantation Biology Research Center (TBRC) at the Massachusetts General Hospital and is a well-respected leader in tolerance and hematopoietic chimerism research. He as a strong track record of mentorship, which now includes several well-established independent surgical investigators. Along with an advisory panel that will include Dr. Alan Flake and Dr. Megan Sykes, Dr. Sachs will provide a rich environment in which the principal investigator can develop into an independent researcher. The research plan will build on the well-established miniature swine model of chimerism and kidney allograft tolerance that has been developed in the laboratory of Dr. Sachs over the past two decades. The goal will be to determine and optimize the parameters required to achieve chimerism and kidney allograft tolerance after in utero hematopoietic cell transplantation in miniature swine. The specific aims are: 1) To compare bone marrow and cytokine mobilized peripheral blood mononuclear cells (CM-PBMC) as a donor cell source for achieving stable multilineage engraftment, 2) Determine if a difference exists between maternal and paternal sources of hematopoietic cells for use as a donor cell source, and 3) Determine the relationship between chimerism and tolerance to donor specific kidney transplantation after birth. This will be the first attempt to systematically analyze factors, in a genetically well-defined large animal model, that might be important to the ultimate clinical success of in utero hematopoietic cell transplantation.