Cytokine primed autologous Mesenchymal Stromal Cells for therapy of colitis.

 描述（由申请人提供）：本资助机会公告（FOA）的目的是促进基于干细胞的治疗，包括间充质干细胞（MSC），用于再生医学。如本FOA中所规定的，鉴于广泛的组织来源、对具有特定性质的亚群的识别以及在细胞培养中扩增时频繁产生功能改变，需要对MSC进行广泛的表征并开发改进的技术。最重要的是，对MSC的正常生物学功能以及它们参与组织修复的机制的理解相对有限。我们的建议非常符合本FOA的目标， 在研究范围内寻求，并将寻求解决与MSC用于治疗克罗恩病的翻译使用密切相关的问题。MSC治疗结肠炎的临床应用可以通过对MSC作为输注细胞产品的作用机制的更好理解而有意义地了解。我们的小组已经产生了令人信服的临床前小鼠数据，强烈支持使用骨髓来源的MSC作为基于细胞的结肠炎治疗，并且γ-干扰素（IFNγ）激活人MSC显著增强其免疫调节特性。在这里，我们提出了一种比较生物学的方法，我们询问免疫和再生机制的作用之间共享的人骨髓间充质干细胞来源于受试者与克罗恩病参加了我们的临床试验，小鼠骨髓间充质干细胞在实验性大肠炎的设置。我们的假设是：（i）MSC组成型表达的特异性因子[CCL 2、IL 6]直接影响结肠炎中针对上皮细胞的免疫应答;（ii）离体IFNγ预处理进一步增强MSC通过PD-L1/PD-1途径和上调其他免疫调节因子[MHCI、MHCII、IDO和CXCL 9/10/11]缓解结肠炎的效力;（iii）MSC和IFNγ引发的衍生物[ICAM-1和整联蛋白组分]的粘附分子表达决定了输注的MSC的体内生物分布，并导致MSC的转录组和免疫可塑性的重编程。重要的是，我们已经证明了我们有能力通过获得FDA IND所需的监管途径，参与基于MSC的早期临床试验NCT 01659762，该试验题为“评估自体骨髓源性间充质基质治疗克罗恩病的I期研究”。该提案的结果将为新的IND申请提供信息，以支持使用IFNγ致敏的MSC治疗结肠炎。

 DESCRIPTION (provided by applicant): The intent of this Funding Opportunity Announcement (FOA) is to facilitate the use of stem cell based therapies, including Mesenchymal Stem Cells (MSCs), for regenerative medicine. As stipulated in this FOA, given the wide range of tissue sources, the recognition of subpopulations with specific properties, and the frequent production of functional alterations upon expansion in cell culture, extensive characterization of MSCs and development of improved techniques are required. Most importantly, there is relatively limited understanding of the normal biological functions of MSCs and the mechanisms by which they participate in tissue repair. Our proposal is exquisitely responsive to the aims of this FOA and it sought after scope of research and will seek to address issues germane to the translational use of MSCs for treatment of Crohn's disease. The clinical use of MSCs for treatment of colitis can be meaningfully informed by an improved understanding of the mechanism of action of MSCs as a transfusional cell product. Our group has generated compelling pre-clinical murine data strongly supporting the use of marrow-derived MSCs as a cell-based therapy for colitis and that γ-interferon (IFNγ) activation of human MSCs significantly augments their immune modulatory properties. We here propose a comparative biology approach where we interrogate immune and regenerative mechanisms of action shared between human MSCs derived from subjects with Crohn's disease enrolled in our clinical trial to murine MSCs in the setting of experimental coliti. Our hypotheses are: (i) specific factors constitutively expressed by MSCs [CCL2, IL6] directly influence the immune response against epithelial cells in colitis; (ii) ex vivo IFNγ priming furthr enhances the potency of MSCs in alleviating colitis via PD-L1/PD-1 pathway and upregulation of other immune regulatory factors [MHCI, MHCII, IDO and CXCL9/10/11]; (iii) adhesion molecule expression by MSC and IFNγ primed derivatives [ICAM-1 and integrin components] determines in vivo biodistribution of transfused MSCs and leads to reprogramming of transcriptome and immune plasticity of MSCs. Importantly, we have already demonstrated our ability to navigate the regulatory pathway required to obtain a FDA IND to engage in a MSC based early phase clinical trial NCT01659762 entitled "A Phase I Study Evaluating Autologous Bone Marrow Derived Mesenchymal Stromal for Crohn's Disease". The results of this proposal will inform a new IND application in support of use of IFNγ primed MSCs for colitis.