Dendritic cells induce tolerance to pancreatic islets

树突状细胞诱导胰岛耐受

• 批准号: 7300779
• 负责人: Ralph Marvin Steinman
• 金额: $ 33.83万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7300779
• 关键词: Adoptive Transfer; Antibodies; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Biology; CD8B1 gene; Cells; Collaborations; DEC-205 receptor; Data; Dendritic Cells; Development; Disease; Engineering; Equilibrium; Human; IL2RA gene; In Vitro; Inbred NOD Mice; Islets of Langerhans; Learning; Ligation; MHC Class II Genes; Maintenance; Modeling; Monoclonal Antibodies; Mus; Numbers; Outcome; Ovalbumin; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Process; Reporter; Sirolimus; Stimulus; T-Lymphocyte; Time; Tissues; Transgenic Mice; Translating; Week; Work; follow-up; in vivo; progenitor; programs; receptor; red fluorescent protein; research study; response; synergism; targeted delivery; uptake

To silence autoimmune disease, we seek a means to expand in mice CD25+ CD4+ foxp3+ regulatory T cells (Treg) that are specific for disease producing autoantigens. We will pursue three themes that have begun through synergisms with Drs. Nussenzweig and Ravetch in this program: 1) The efficiency of antigen presentation in vivo can be greatly increased by targeted delivery of antigen within monoclonal antibodies to uptake receptors on dendritic cell (DCs). 2) A pivotal feature to the outcome of antigen presentation is the state of differentiation or maturation of the DC; this can be enhanced or blocked through selective ligation of activating and inhibitory FcyR respectively. 3) DCs are specialized antigen presenting cells for CD25+ foxp3+ Treg, being able to drive their expansion with maintenance of foxp3 expression and function (5) and to convert CD25- foxp3- T cells into CD25+ foxp3+ T reg (preliminary data). Therefore we will identify DC receptors, subsets and maturation states that are required to control the development and maintenance of antigen-specific T reg in the peripheral tissues of mice. Aim 1 will determine the DC requirements for the expansion of CD25+ CD4+ foxp3+ antigen-specific Treg in vivo, pursuing initial evidence that the 33D1 receptor on CDS- DCs is an effective pathway. Aim 2 will determine the DC requirements for the differentiation of CD25+ CD4+ foxp3+ antigen-specific Treg in vivo from CD25- CD4+ foxpS- progenitors, pursuing initial evidence that the DEC-205 receptor on CD8+ DCs is an effective pathway and that TGFp works in concert with antigen presenting DCs to generate typical antigen-specific foxp3+ T reg. Aim 3 will induce, expand and maintain antigen-specific Tregs from a naive polyclonal T cell repertoire, including capacity of DC-targeting antibodies to ligate activating and inhibitory Feyreceptors. By harnessing the biology of DCs in vivo, particularly by targeting antigens within monoclonal antibodies to uptake receptors expressed on DCs, and by controlling the state of differentiation or maturation of DCs, we will be able to define the priniciples for generating large numbers of disease specific regulatory T cells in intact mice. This should in turn translate into new targeted therapies and products required to control autoimmunity in patients in a much more disease specific manner than has previously been feasible.

为了抑制自身免疫性疾病，我们寻找了一种在小鼠体内扩增CD25+CD4+Foxp3+调节性T细胞的方法 (Treg)对产生自身抗原的疾病具有特异性。我们将继续探讨已经开始的三个主题 通过与Nussenzweig博士和Ravetch博士在这个项目中的协同作用：1)抗原的效率 通过靶向递送抗原单抗可大大提高体内的呈递能力 树突状细胞(DC)上的摄取受体。2)抗原呈递结果的一个关键特征是 DC分化或成熟的状态；这可以通过选择性地结扎DC来增强或阻止 分别激活和抑制FcyR。3)树突状细胞是CD25+的特异性抗原提呈细胞 Foxp3+Treg，能够通过维持Foxp3的表达和功能来驱动它们的扩张(5)和 将CD25-Foxp3-T细胞转化为CD25+Foxp3+T细胞(初步数据)。因此，我们将确定DC 控制细胞发育和维持所需的受体、亚群和成熟状态 小鼠外周组织中的抗原特异性T细胞。目标1将确定以下项目的DC要求 CD25+CD4+Foxp3+抗原特异性Treg在体内的扩增，寻求33D1的初步证据 CDS-DC上的受体是一条有效的途径。目标2将确定以下项目的DC要求 体内CD25+CD4+Foxp3+抗原特异性Treg与CD25-CD4+foxpS-祖细胞的分化 寻求CD8+DC表面DEC-205受体是有效途径的初步证据 与抗原提呈树突状细胞协同工作，产生典型的抗原特异性Foxp3+T受体。目标3将 从一个朴素的多克隆T细胞库中诱导、扩增和维持抗原特异性Tregs，包括 DC靶向抗体连接激活和抑制Fey受体的能力。通过利用 体内树突状细胞的生物学，特别是通过靶向摄取受体的单抗中的抗原 在DC上表达，通过控制DC的分化或成熟状态，我们将能够 确定在完整小鼠中产生大量疾病特异性调节性T细胞的原理。这 应该反过来转化为控制患者自身免疫所需的新的靶向治疗和产品 以一种比以前可行的更具疾病特异性的方式。