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
基本信息
- 批准号:9314221
- 负责人:
- 金额:$ 34.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Adoptive TransferAntibody FormationAttenuatedAutoantibodiesAutoantigensB-Cell ActivationB-LymphocytesBiological Response Modifier TherapyC3AR1 geneC5a anaphylatoxin receptorCD4 Positive T LymphocytesCellsCellular biologyCharacteristicsClinicalCollaborationsComplement 3aComplement 5aDataDendritic CellsDiseaseDisease ProgressionEffector CellEventExperimental Autoimmune EncephalomyelitisFOXP3 geneG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGenerationsHumanHyperplasiaImmuneImmune responseImmunoglobulin Class SwitchingImmunoglobulin Switch RecombinationImmunosuppressionImmunosuppressive AgentsInbred BALB C MiceInflammatoryInterleukin-6Knock-outKnowledgeLuciferasesLymphoidMacrophage ActivationMesenchymal Stem CellsMethodsModelingMouse StrainsMultiple SclerosisMusOutcomePathogenesisPatientsPeritonealPlayPristaneProductionProteinuriaPublishingReceptor SignalingRegulatory T-LymphocyteResistanceRoleRouteSignal TransductionSpleenSurfaceSystemic Lupus ErythematosusT cell regulationT-LymphocyteTNFRSF5 geneTNFSF5 geneTherapeuticTherapeutic EffectTherapeutic InterventionToll-like receptorsTransforming Growth Factor betaTreatment EfficacyUp-RegulationWorkautocrineautoreactive B cellcell typecytokineimmunoregulationin vivoinsightmouse modelnovelpreventprogramspublic health relevancereceptorresponseunpublished worksvirtual
项目摘要
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(由适用提供):作为一种可以抑制鼠SLE模型和SLE患者试验的生物疗法,间充质干细胞(MSC)一直在越来越多的希望。然而,人类试验中效率的主要局限性是
它们的有益作用(Sledai评分和蛋白尿)是部分的,并且寿命短。尽管MSC在很大程度上通过诱导FOXP3+ T调节细胞(ITREGS)发挥了免疫抑制作用,但尚未澄清其免疫抑制与Treg免疫抑制的关系。此外,如何延长MSC免疫抑制并维持其长期生产的Treg仍然未知。我们最近的工作发现,在Th1和Th17细胞激活中,先前未识别的事件是,内源性产生的C3A和C5A的树突状细胞(DC)-CD4+细胞伴侣,并上调其C3A和C5A受体(C3AR/C5AR)G蛋白蛋白耦合受体(GPCRS)的表面表达。局部C3A和C5A在相互作用的DC-CD4+细胞合作伙伴上上调C3AR和C5AR。我们发现,该GPCR信号不仅提供了共同刺激,而且还提供了与Th1和Th17细胞反应不可或缺的生存信号。重要的是,我们最近发表的工作表明,在幼稚的CD4+细胞中缺乏C3AR/C5AR信号传导可实现自动感应性TGF-β信号传导,反映了CD4+细胞CD40L上调和IL-6产生,并导致TREG产生。这些发现的一个重要的临床结果是,相比之下,过去的困难在产生人类的treg中,从而行使强大的抑制作用活动并且稳定,我们的发现现在为实现这一目标提供了途径。我们的初步研究与SLE相关,现在表明,B细胞中缺乏C3AR/C5AR信号传导,废除CD40上调和IL-6产生,减少AB的产生和类切换重组(CSR),并抑制TLR信号。与此相一致,我们发现破坏C3AR/C5AR信号传导几乎消除了Pristane诱导的鼠SLE模型中的疾病。 MSC(例如CD4+细胞和DC)表达C3AR/C5AR。在未发表的工作中,我们发现将C3AR/C5AR信号破坏到Tregs维持Treg稳定性中,持续了7个月。我们还开发了精确量化C3AR/C5AR信号传导对MSC稳定性的影响的方法,并评估MSC与体内Tregs的相互作用。该提案的核心是它是我们实验室与MSC生物学先驱Arnold Caplan的合作。该目标是针对最佳利用MSC和Treg免疫抑制来控制SLE的。独特的合作将与利用我们新颖的小鼠菌株的鼠SLE模型以及利用我们对人类Treg谱系承诺的新见解的SLE患者进行。
项目成果
期刊论文数量(0)
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{{ truncateString('MELVIN EDWARD MEDOF', 18)}}的其他基金
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 - 财政年份:2015
- 资助金额:
$ 34.87万 - 项目类别:
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:
9105570 - 财政年份:2015
- 资助金额:
$ 34.87万 - 项目类别:
Local Complement Synthesis and Signaling by Endothelial and Inflammatory Cells
内皮细胞和炎症细胞的局部补体合成和信号传导
- 批准号:
8373385 - 财政年份:2012
- 资助金额:
$ 34.87万 - 项目类别:
Local Complement Synthesis and Signaling by Endothelial and Inflammatory Cells
内皮细胞和炎症细胞的局部补体合成和信号传导
- 批准号:
8517802 - 财政年份:2012
- 资助金额:
$ 34.87万 - 项目类别:
Local Complement Synthesis and Signaling by Endothelial and Inflammatory Cells
内皮细胞和炎症细胞的局部补体合成和信号传导
- 批准号:
8678990 - 财政年份:2012
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$ 34.87万 - 项目类别:
Pathogenic Mechanisms Underlying Diabetic Retinopathy
糖尿病视网膜病变的发病机制
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6904443 - 财政年份:2004
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Pathogenic Mechanisms Underlying Diabetic Retinopathy
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7287402 - 财政年份:2004
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Pathogenic Mechanisms Underlying Diabetic Retinopathy
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6762097 - 财政年份:2004
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Pathogenic Mechanisms Underlying Diabetic Retinopathy
糖尿病视网膜病变的发病机制
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