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疗法的使用，包括间充质干细胞(MSCs)，用于再生医学。正如本FOA所规定的，鉴于组织来源的广泛性、对具有特定特性的亚群的认识以及在细胞培养扩大时频繁产生的功能变化，需要对MSCs进行广泛的表征并开发改进的技术。最重要的是，对骨髓间充质干细胞的正常生物学功能以及它们参与组织修复的机制的了解相对有限。我们的建议巧妙地回应了本FOA和它的目标 追求研究范围，并将寻求解决与将骨髓间充质干细胞用于治疗克罗恩病的翻译使用密切相关的问题。通过对骨髓间充质干细胞作为一种输血细胞产物的作用机制的更深入的了解，可以对骨髓间充质干细胞治疗结肠炎的临床应用提供有意义的信息。我们的团队已经产生了令人信服的临床前小鼠数据，有力地支持将骨髓来源的骨髓间充质干细胞用作结肠炎的细胞疗法，并且人骨髓间充质干细胞的干扰素(γγ)激活显著增强了其免疫调节特性。我们在这里提出了一种比较生物学的方法，我们询问了来自临床试验中登记的克罗恩病患者的人MSCs和实验性结肠炎环境中的小鼠MSCs之间共享的免疫和再生作用机制。我们的假设是：(I)MSCs[CCL2，IL6]表达的特异性因子直接影响结肠炎对上皮细胞的免疫应答；(Ii)体外干扰素γ通过PD-L1/PD-1途径和上调其他免疫调节因子[MHCI，MHCII，IDO和CXCL9/10/11]进一步增强MSCs缓解结肠炎的能力；(Iii)MSCs和干扰素γ启动的衍生物[ICAM-1和整合素成分]表达的黏附分子决定了输入的MSCs的体内生物分布，并导致转录组的重新编程和MSCs的免疫可塑性。重要的是，我们已经证明了我们有能力通过所需的调控途径获得FDA IND，以参与一项基于MSC的早期临床试验NCT01659762，题为“评估自体骨髓间充质基质治疗克罗恩病的I阶段研究”。这项建议的结果将为一种新的IND应用程序提供信息，以支持使用干扰素γ激活的MSCs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.