In Utero Tolerance Induction in Miniature Swine

描述（由申请人提供）： 该五年计划的目的是使主要研究者能够通过使用子宫内造血细胞移植获得临床相关的耐受诱导大型动物模型的新技能和经验。 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，并补充儿科手术、实体器官移植和胎儿治疗的临床培训。 这种独特的专业知识组合将有望转化为一种临床相关的方法来治疗产前诊断的疾病，一旦在子宫内建立了供体特异性耐受，这些疾病可以在出生后通过造血或实体器官移植治疗。 大卫萨克斯博士将在整个研究计划中指导首席研究员。Sachs博士是马萨诸塞州总医院移植生物学研究中心（TBRC）的主任，是耐受性和造血嵌合体研究领域备受尊敬的领导者。 他有着良好的指导记录，现在包括几个成熟的独立外科调查员。 沿着的顾问小组将包括艾伦·弗莱克博士和梅根·赛克斯博士，萨克斯博士将提供一个丰富的环境，使主要研究者能够发展成为一名独立的研究人员。 该研究计划将建立在嵌合体和肾脏移植耐受性的成熟小型猪模型的基础上，该模型是在过去二十年中在Sachs博士的实验室中开发的。 目的是确定和优化小型猪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。 具体目标是：1）比较骨髓和细胞因子动员的外周血单核细胞（CM-PBMC）作为供体细胞来源以实现稳定的多谱系植入，2）确定用作供体细胞来源的造血细胞的母体和父亲来源之间是否存在差异，和3）确定出生后嵌合状态和对供体特异性肾移植的耐受性之间的关系。 这将是第一次尝试系统地分析因素，在一个遗传定义明确的大型动物模型，这可能是重要的，在子宫内造血细胞移植的最终临床成功。

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.