Local inhibition of complement to improve MSC-based therapy for diabetes

 描述（由申请人提供）：间充质干细胞（MSC）正在多项临床试验中进行测试，以治疗炎症和退行性疾病，并正在开发作为一种新的方法，以延长移植的同种异体胰岛的生存期，用于治疗糖尿病。尽管通常认为MSC是免疫豁免的，但在动物和人类中也经常观察到，这些MSC在施用后几天内神秘地消失。最近使用MSC的临床试验的结果也令人失望，这表明与先前的观点相反，MSC在施用后迅速被宿主排斥，并且必须改进目前基于MSC的疗法才能成功。我们最近发表的工作和最新未发表的研究表明，在给药后，体外扩增的MSC激活补体，这是先天免疫系统的重要组成部分，主要作用是攻击宿主的任何外来物。活化的补体系统然后通过多种机制直接和间接攻击MSC，导致MSC活力和效力降低。在这个项目中，使用一个已建立的模型，其中人胰岛同种异体移植物与人MSC共移植到人源化小鼠中，我们将测试我们新开发的“涂抹”方法对MSC/胰岛共移植结果的影响，该方法使用FDA批准的药物局部抑制MSC上的补体激活。我们还将评估第二种FDA批准的药物的协同作用，该药物上调MSC上天然细胞表面补体抑制剂的表达以局部抑制补体。此外，我们将阐明补体介导的直接和间接攻击间充质干细胞的机制。这些研究将有助于阐明MSC被接受者排斥的机制，为将这些简单的策略转化为治疗提供理论基础。 在不久的将来，作为改善MSC/胰岛共移植治疗糖尿病的结果的新方法，可能有助于开发新方法来改善目前基于MSC的治疗其他炎症和退行性疾病的结果。

 DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSCs) are being tested in multiple clinical trials to treat inflammatory and degenerative diseases and are being developed as a new approach to prolonging the survival of transplanted allogeneic islets for treating diabetes. Although it is commonly believed that MSCs are immunoprivileged, it is also commonly observed, in both animals and humans, those MSCs mysteriously disappear within days after administration. Recent results from clinical trials using MSCs have also been disappointing, suggesting that, contrary to previous belief, MSCs are rapidly rejected by the host after administration and that current MSC- based therapies must be improved to be successful. Our recently published work and latest unpublished studies indicate that, after administration, in vitro expanded MSCs activate complement, an important component of the innate immune system with the primary role of attacking anything foreign to the host. The activated complement system then directly and indirectly attacks MSCs through multiple mechanisms, leading to reduced MSC viability and potency. In this proposed project, using an established model in which human islet allografts are co-transplanted with human MSCs into humanized mice, we will test the effect on the outcome of MSC/islet co-transplantation of our newly developed "painting" approach to locally inhibit complement activation on MSCs using an FDA-approved drug. We will also evaluate the synergetic effect of a second FDA-approved drug that upregulates expression of a native cell-surface complement inhibitor on MSCs to locally inhibit complement. Furthermore, we will elucidate the mechanisms underlying complement- mediated direct and indirect attack on MSCs. These studies will help clarify the mechanisms by which administered MSCs are rejected by the recipient, provide rationales for translating these simple strategies into the clinic in the near future as new approaches for improving outcome of MSC/islet co-transplantation for treating diabetes, and might help in the development of new approaches to improve the outcome of current MSC-based therapies for other inflammatory and degenerative diseases.