Dendritic cells induce tolerance to pancreatic islets

树突状细胞诱导胰岛耐受

• 批准号: 7645165
• 负责人: Ralph Marvin Steinman
• 金额: $ 34.25万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645165
• 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.

为了沉默自身免疫性疾病，我们寻求一种在小鼠中扩增CD 25 + CD 4 + foxp 3+调节性T细胞的方法， （Treg），其特异于疾病产生自身抗原。我们将探讨三个主题， 通过与Nussenzweig和Ravetch博士在该项目中的协同作用：1）抗原的效率 通过在单克隆抗体内靶向递送抗原， 树突状细胞（DC）上的摄取受体。2)抗原呈递结果的关键特征是 DC的分化或成熟状态;这可以通过选择性连接 分别激活和抑制Fc γ R。3)DC是CD 25+的特异性抗原呈递细胞 foxp 3 + Treg，能够在维持foxp 3表达和功能的情况下驱动其扩增（5），以及 将CD 25-foxp 3- T细胞转化为CD 25 + foxp 3 + T reg（初步数据）。因此，我们将识别DC 受体，亚群和成熟状态，需要控制的发展和维护 小鼠外周组织中的抗原特异性T reg。目标1将确定 在体内扩增CD 25 + CD 4 + foxp 3+抗原特异性Treg，追求33 D1 CDS-DCs上的CDS-R受体是一个有效的途径。目标2将确定 从CD 25-CD 4 + foxp 3-祖细胞体内分化CD 25 + CD 4 + foxp 3+抗原特异性Treg， 寻求初步证据表明CD 8 + DC上的DEC-205受体是一种有效途径，并且TGFp 与抗原呈递DC协同工作以产生典型的抗原特异性foxp 3 + T reg. Aim 3将 从幼稚多克隆T细胞库诱导、扩增和维持抗原特异性T细胞，包括 DC靶向抗体连接激活性和抑制性Fe γ受体的能力。通过利用 体内DC生物学，特别是通过将单克隆抗体内的抗原靶向摄取受体 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加疾病特异性的方式。