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，我们寻求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。我们将追求已经开始的三个主题 通过与博士的协同作用。 Nussenzweig和Ravetch在这个程序中：1）抗原的效率 通过单克隆抗体内抗原的靶向递送可以大大增加体内呈递 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的分化或成熟状态；这可以通过选择性连接来增强或阻断 分别激活和抑制FcyR。 3) DCs是专门针对CD25+的抗原呈递细胞 Foxp3+ Treg，能够通过维持 Foxp3 表达和功能来驱动其扩展 (5) 和 将CD25-foxp3-T细胞转化为CD25+foxp3+Treg（初步数据）。因此我们将确定 DC 控制发育和维持所需的受体、子集和成熟状态 小鼠外周组织中的抗原特异性 T reg。目标 1 将确定 DC 要求 CD25+ CD4+ Foxp3+ 抗原特异性 Treg 在体内的扩增，寻求初步证据表明 33D1 CDS-DCs上的受体是一种有效的途径。目标 2 将确定 DC 要求 CD25+CD4+foxp3+抗原特异性Treg在体内与CD25-CD4+foxpS-祖细胞的分化， 寻求初步证据表明 CD8+ DC 上的 DEC-205 受体是一种有效的途径，并且 TGFp 与抗原呈递 DC 协同工作，产生典型的抗原特异性 Foxp3+ T reg。目标3将 诱导、扩增和维持来自初始多克隆 T 细胞库的抗原特异性 Tregs，包括 DC 靶向抗体连接激活性和抑制性 Fey 受体的能力。通过利用 DC 体内生物学，特别是通过将单克隆抗体内的抗原靶向摄取受体 在 DC 上表达，通过控制 DC 的分化或成熟状态，我们将能够 定义了在完整小鼠中产生大量疾病特异性调节 T 细胞的原理。这 反过来应该转化为控制患者自身免疫所需的新的靶向疗法和产品 以比以前可行的更加针对特定疾病的方式。