Optimizing mesenchymal stem cell and Treg immunosuppression for controlling SLE

优化间充质干细胞和 Treg 免疫抑制以控制 SLE

• 批准号: 8964783
• 负责人: MELVIN EDWARD MEDOF
• 金额: $ 34.87万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-04 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8964783
• 关键词: Antibodies; Antibody Formation; Attenuated; Autoantibodies; Autoantigens; B-Cell Activation; B-Lymphocytes; Biological Response Modifier Therapy; C5a anaphylatoxin receptor; CD4 Positive T Lymphocytes; Cells; Clinical; Collaborations; Complement 3a; Complement 5a; Data; Dendritic Cells; Disease; Disease Progression; Effector Cell; Event; Experimental Autoimmune Encephalomyelitis; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Generations; Human; Hyperplasia; Immune; Immune response; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunosuppression; Immunosuppressive Agents; Inbred BALB C Mice; Inflammatory; Interleukin-6; Knock-out; Knowledge; Life; Luciferases; Lymphoid; Macrophage Activation; Mesenchymal Stem Cells; Methods; Modeling; Mouse Strains; Multiple Sclerosis; Mus; Outcome; Pathogenesis; Patients; Peritoneal; Play; Pristane; Production; Proteinuria; Publishing; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Resistance; Role; Route; Signal Transduction; Sorting - Cell Movement; Spleen; Surface; Systemic Lupus Erythematosus; T cell regulation; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Toll-like receptors; Treatment Efficacy; Up-Regulation; Work; autocrine; cell type; cytokine; in vivo; insight; novel; prevent; programs; public health relevance; receptor; response; stem cell biology; unpublished works

 DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSCs) have been gaining increasing promise as a biotherapy that can suppress disease in murine SLE models and in an initial trial of SLE patients. Major limitations of efficacy in the human trial, however, were that their beneficial effects (SLEDAI scores and proteinuria) were partial and were short lived. While MSCs exert their immunosuppressive effects in large part via the induction of Foxp3+ T regulatory cells (iTregs), the relationship of their immunosuppression to that of Treg immunosuppression has not been clarified. Moreover, how to prolong MSC immunosuppression and sustain the Tregs they produce long term remains unknown. Our recent work found that a previously unrecognized event in Th1 and Th17 cell activation is that dendritic cell (DC)-CD4+ cell partners endogenously produce C3a and C5a and up-regulate their surface expression of C3a and C5a receptors (C3aR/C5aR) G protein coupled receptors (GPCRs). The local C3a and C5a ligate up- regulated C3aR and C5aR on the interacting DC-CD4+ cell partners. We found that this GPCR signaling provides not only costimulatory but also survival signals that are integral to Th1 and Th17 cell responses. Importantly, our recently published work showed that the absent C3aR/C5aR signaling into naïve CD4+ cells enables auto-inductive TGF-ß signaling which represses CD4+ cell CD40L up-regulation and IL-6 production and leads to the generation of Tregs. An important clinical outcome of these findings was that in contrast difficulties in the past in generating human Tregs that exert robust suppressor activity and are stable, our findings now provide a route to achieve this. Centrally relevant to SLE, our preliminary studies now show that absent C3aR/C5aR signaling in B cells, abolishes CD40 up-regulation and IL-6 production, reduces Ab production and class switching recombination (CSR), and suppresses TLR signaling. Consistent with this, we have found that disrupting C3aR/C5aR signaling virtually abolishes disease in the pristane induced murine SLE model. MSCs, like CD4+ cells and DCs, express C3aR/C5aR. In unpublished work, we have found that disrupting C3aR/C5aR signaling into Tregs sustains Treg stability in vivo for >7 months. We additionally have developed methods to precisely quantify the effects of disrupted C3aR/C5aR signaling on MSC stability and to assess the interaction of MSCs with Tregs in vivo. The centerpiece of this proposal is that it is a collaboration between our lab and that of Arnold Caplan, a pioneer in MSC biology. The Aims are directed at optimally harnessing MSC and Treg immunosuppression for controlling SLE. The unique collaboration will be conducted with murine SLE models exploiting our novel mouse strains and with SLE patients exploiting our new insights on human Treg lineage commitment.

 描述(申请人提供)：间充质干细胞(MSCs)作为一种生物疗法在小鼠SLE模型和SLE患者的初步试验中得到了越来越多的希望。然而，在人体试验中，疗效的主要限制是 它们的有益作用(SLEDAI评分和蛋白尿)是部分的，而且是短暂的。虽然MSCs在很大程度上是通过诱导Foxp3+T调节细胞(ITregs)发挥免疫抑制作用的，但其免疫抑制与Treg免疫抑制的关系尚不清楚。此外，如何延长MSC的免疫抑制并长期维持它们产生的Treg仍是未知的。我们最近的工作发现，在Th1和Th17细胞激活中，一个以前未被发现的事件是树突状细胞(DC)-CD4+细胞伙伴内源性产生C3a和C5a，并上调其表面C3a和C5a受体(C3aR/C5aR)G蛋白偶联受体(GPCRs)的表达。局部C3a和C5a连接在相互作用的DC-CD4+细胞伙伴上上调的C3aR和C5aR。我们发现，这种GPCR信号不仅提供了共刺激信号，而且还提供了Th1和Th17细胞反应所必需的生存信号。重要的是，我们最近发表的工作表明，缺失的C3aR/C5aR信号进入幼稚的CD4+细胞使自身诱导的转化生长因子-B信号能够抑制CD4+细胞CD40L上调和IL-6的产生，并导致Tregs的产生。这些发现的一个重要临床结果是，与过去在产生具有强大抑制活性且稳定的人类Tregs方面的困难相反，我们的发现现在提供了一条实现这一目标的途径。我们的初步研究表明，与SLE中心相关的是，B细胞中C3aR/C5aR信号缺失，取消CD40上调和IL-6产生，减少抗体产生和类转换重组(CSR)，并抑制TLR信号。与此一致，我们发现在Pristane诱导的小鼠SLE模型中，干扰C3aR/C5aR信号实际上可以消除疾病。间充质干细胞与CD4+细胞和DC一样，表达C3aR/C5aR。在未发表的工作中，我们发现干扰C3aR/C5aR信号进入Treg可以维持Treg在体内7个月的稳定性。此外，我们还开发了一些方法来精确量化C3aR/C5aR信号中断对MSC稳定性的影响，并在体内评估MSCs与Tregs的相互作用。这项提议的核心是，它是我们的实验室和MSC生物学先驱阿诺德·卡普兰的合作。其目标是以最佳方式利用MSC和Treg免疫抑制来控制SLE。这一独特的合作将与利用我们新的小鼠品系的小鼠SLE模型和利用我们对人类Treg血统承诺的新见解的SLE患者进行。