Manipulation of MHC expression using TGF-beta2 to reduce mesenchymal stem cell immunogenicity

项目总结/摘要 拟议的指导研究科学家发展奖（K 01）将为候选人阿利克斯博士提供 Berglund，DVM，博士，具有必要的知识，培训和经验，成为一个独立的 在免疫学和间充质干细胞（MSC）生物学领域的翻译生物医学研究员。 骨髓间充质干细胞是一种有前途的细胞来源，用于治疗炎症和免疫介导的疾病。同种异体疗法 将提供具有成本效益和有效的治疗，但目前受到受体免疫排斥的阻碍， 供体MSC表达错配的主要组织相容性复合体（MHC）分子。MSC是强有力的 然而，免疫调节和操纵MHC表达可能足以使供体MSC 逃避受体免疫反应这一建议的中心假设，这是由强大的支持， 初步研究表明，用转化生长因子-β2（TGF-β2）处理MSCs可下调MHC I 和MHC II基因转录，从而降低MHC错配MSC的体内免疫原性。的 本项目的目的是：1）确定TGF-β2如何下调MSC中MHC的表达; 2）确定 TGF-β2处理如何影响MSC体内免疫原性。鼠和马MSC将用于 阐明TGF-β2信号通路，以增加对人类的翻译潜力（目的1）和非炎性 和炎症小鼠模型将用于分析免疫系统如何响应TGF-β2处理的 体内MSC（目的2）。完成拟议的研究是提高疗效的第一步， 同种异体MSCs临床应用的安全性。为了实现这些目标，Berglund博士将利用她的背景， 间充质干细胞生物学，免疫学和大型动物模型，通过发展分子生物学， 免疫学技术、体内同种免疫应答分析和鼠模型的利用。博士 Berglund的指导团队结合了免疫学、间充质干细胞和遗传学方面的专业知识， 帮助她过渡到一个独立的翻译生物医学研究员。这项工作将完成 主要是在北卡罗来纳州州立大学兽医学院，这是非常有资格， 培训翻译临床科学家，在北卡罗来纳大学教堂山分校的额外工作。

PROJECT SUMMARY/ABSTRACT The proposed Mentored Research Scientist Development Award (K01) will provide the candidate, Dr. Alix Berglund, DVM, PhD, with the necessary knowledge, training, and experience to become an independent translational biomedical researcher in the fields of immunology and mesenchymal stem cell (MSC) biology. MSCs are a promising cell source for treating inflammatory and immune-mediated diseases. Allogeneic therapy would provide cost-effective and efficient treatment, but is currently hindered by recipient immune rejection of donor MSCs expressing mismatched-major histocompatibility complex (MHC) molecules. MSCs are strongly immunomodulatory, however, and manipulation of MHC expression may be sufficient to allow donor MSCs to evade recipient immune responses. The central hypothesis of this proposal, which is supported by strong preliminary research, is that treating MSCs with transforming growth factor-β2 (TGF-β2) downregulates MHC I and MHC II gene transcription thereby reducing the in vivo immunogenicity of MHC-mismatched MSCs. The aims of this project are to 1) Identify how TGF-β2 downregulates MHC expression in MSCs and 2) Determine how TGF-β2 treatment affects MSC immunogenicity in vivo. Both murine and equine MSCs will be utilized to elucidate TGF-β2 signaling pathways to increase translational potential to humans (Aim 1) and non-inflammatory and inflammatory murine models will be used to analyze how the immune system responds to TGF-β2-treated MSCs in vivo (Aim 2). Completion of the proposed research is a first step towards improving the efficacy and safety of allogeneic MSCs for clinical use. To accomplish these aims, Dr. Berglund will build on her background in mesenchymal stem cell biology, immunology, and large animal models by developing expertise in molecular immunology techniques, in vivo alloimmune response analysis, and the utilization of murine models. Dr. Berglund's mentoring team has combined expertise in immunology, mesenchymal stem cells, and genetics to facilitate her transition to an independent translational biomedical researcher. This work will be completed primarily at the North Carolina State University College of Veterinary Medicine, which is eminently qualified to train translational clinician scientists, with additional work at the University of North Carolina-Chapel Hill.