Dendritic cell directed T cell negative regulation for treating autoimmunity

树突状细胞定向 T 细胞负调节治疗自身免疫

• 批准号: 7776898
• 负责人: CHENTHAMARAKSHAN VASU
• 金额: $ 38.86万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-24 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7776898
• 关键词: Adopted; Adverse effects; Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigens; Attention; Autoimmune Diseases; Autoimmune Process; Autoimmune thyroiditis; Autoimmunity; Binding; Bone Marrow; CD28 gene; CD4 Positive T Lymphocytes; CD80 gene; CDR1 gene; Cell Communication; Cell physiology; Cells; Characteristics; Clinical; Complementary DNA; Complex; Dendritic Cells; Disease; Disease model; Down-Regulation; Effectiveness; Engineering; Event; Figs - dietary; Future; Generations; Goals; Graft Rejection; Hashimoto Disease; Homeostasis; Immune; Immune System Diseases; Immunization; Immunosuppressive Agents; In Vitro; Inbred NOD Mice; Individual; Inflammatory Response Pathway; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Knock-in Mouse; Lead; Length; Life; Ligands; Ligation; Longevity; Mediating; Memory; Methods; Modeling; Monitor; Mus; Nature; Opportunistic Infections; Orphan; Ovalbumin; Pathway interactions; Peptides; Physiologic pulse; Process; Property; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Reporting; Rest; Risk; Role; Safety; Signal Transduction; Specificity; Staging; Stem cells; Surface; Synapses; System; T cell differentiation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Therapeutic Uses; Thyroglobulin; Time; Tissues; Transgenic Organisms; Wild Type Mouse; cellular engineering; cost; cytokine; experience; high voltage electron microscopy; in vitro testing; in vivo; inhibitor/antagonist; interest; mouse model; mutant; overexpression; prevent; public health relevance; receptor; receptor expression; research study; response; tool

DESCRIPTION (provided by applicant): Costimulatory pathways are considered essential for T cell activation and differentiation. Manipulating these signals on antigen encountered T cells is a most attractive approach for inducing antigen specific tolerance to prevent and suppress autoimmunity. Co-inhibitors/repressor-receptors (negative regulators) that are upregulated significantly on activated T cells, and have been the molecules of attention as targets for therapy in last several years. Induction of antigen specific tolerance depends on concurrent engagement of the TCR and one or more of these repressor-receptors. Interestingly, our studies have shown that this T cell tolerance is mostly associated with an induction and/or expansion of antigen specific regulatory T cells (Tregs). Antigen specific Tregs can suppress effector T cell response and provide long-term sustained protection from autoimmunity. Our hypothesis is that dominant engagement of repressor-receptors along with TCR on antigen specific T cells using dendritic cells (DCs) engineered to stably overexpress negative regulatory ligands will induce effective long-lasting antigen specific T cell tolerance. Our studies have so far demonstrated that antigen specific engagement of repressor-receptors on T cells by DC directed approaches could induce significant suppression of antigen specific T cell response and generation of hypo- proliferative T cells with the ability to produce large amounts of suppressor cytokines such as IL-10 and TGF-21 both in vitro and in vivo. Therefore, the approach of stable exogenous over-expression of ligands, B7.1wa, PD-L1, and HVEM-CRD1 that are specific for T cell repressor-receptors, CTLA-4, PD-1 and BTLA is adopted for generating tolerogenic APCs. These DCs can present antigen to T cells and simultaneously engage their repressor-receptors with an enhanced strength. These tolerogenic DCs could induce profound suppression of antigen specific T cell and pro-inflammatory cytokine responses, but enhanced anti- inflammatory cytokine responses. The exceptional antigen presenting properties of DCs combined with the engineered DC's ability to predominantly engage repressor-receptors on activated T cells are exploited in this system. This negative regulatory ligand over-expressing DCs can also be a powerful tool to study the effect of enhanced engagement of T cell repressor-receptors during the antigen presentation. This study will be aimed at 1) understanding the potential of DCs that are over-expressing ligands for T cell repressor- receptors to induce and maintain antigen specific T cell hypo-responsiveness and tolerance, 2) understanding the mechanism of enhanced T cell repressor-receptor ligation induced signaling and the associated effects on effector T cell function and differentiation, and 3) characterizing the therapeutic potential of negative regulator over-expressing DCs using a T cell mediated autoimmune disease model. Public Health Relevance: This project will exploit the professional antigen presenting properties of dendritic cells (DCs) and the powerful inhibitory signals of T cell repressor-receptors (negative regulators) combined to achieve the goal of modulating T cell function and inducing antigen specific T cell hypo-responsiveness and tolerance. This will be achieved by exogenously over-expressing DCs with ligands specific for T cell repressor-receptors (CTLA-4, PD-1 and BTLA) and loading them with the antigen(s) of interest for actively suppressing T cells though delivering inhibitory signals during antigen presentation. Inducing antigen specific T cell tolerance by generating adaptive hypo-responsive and regulatory T cells will be the most effective way of treating autoimmunity and graft rejection and, we believe that, our proposed approach will be one of the most efficient ways of achieving that goal. Moreover, this approach would be one of the efficient ways to study the effect of enhanced engagement of T cell repressor-receptors during antigen presentation. Our study will have an immense impact on approaches to treat autoimmunity without risking opportunistic infections as well as by eliminating the need for a life-long treatment using general immunosuppressive agents.

描述（由申请人提供）：共刺激途径被认为对于 T 细胞激活和分化至关重要。操纵遇到抗原的 T 细胞上的这些信号是诱导抗原特异性耐受以预防和抑制自身免疫的最有吸引力的方法。协同抑制剂/阻遏受体（负调节因子）在活化的 T 细胞上显着上调，并且在过去几年中已成为备受关注的治疗靶点分子。抗原特异性耐受的诱导取决于 TCR 和这些阻遏受体中的一种或多种的同时参与。有趣的是，我们的研究表明，这种 T 细胞耐受性主要与抗原特异性调节性 T 细胞 (Treg) 的诱导和/或扩增有关。抗原特异性 Tregs 可以抑制效应 T 细胞反应并提供长期持续的自身免疫保护。我们的假设是，使用经过工程改造以稳定过度表达负调节配体的树突状细胞（DC），阻遏受体与抗原特异性 T 细胞上的 TCR 显着结合，将诱导有效、持久的抗原特异性 T 细胞耐受。迄今为止，我们的研究已经证明，通过 DC 定向方法，T 细胞上的阻遏受体 - 抗原特异性结合可以显着抑制抗原特异性 T 细胞反应，并产生低增殖性 T 细胞，并能够在体外和体内产生大量抑制性细胞因子，例如 IL-10 和 TGF-21。因此，采用稳定外源过表达 T 细胞阻遏受体 CTLA-4、PD-1 和 BTLA 特异的配体 B7.1wa、PD-L1 和 HVEM-CRD1 的方法来产生耐受性 APC。这些 DC 可以向 T 细胞呈递抗原，同时以增强的强度与其阻遏受体结合。这些耐受性 DC 可以诱导抗原特异性 T 细胞和促炎细胞因子反应的深度抑制，但增强抗炎细胞因子反应。该系统利用了 DC 的特殊抗原呈递特性以及工程化 DC 主要与活化 T 细胞上的阻遏受体结合的能力。这种负调节配体过度表达的 DC 也可以成为研究抗原呈递过程中 T 细胞阻遏受体结合增强效果的有力工具。本研究旨在 1) 了解过度表达 T 细胞阻遏受体配体的 DC 诱导和维持抗原特异性 T 细胞低反应性和耐受性的潜力，2) 了解增强 T 细胞阻遏受体连接诱导信号传导的机制以及对效应 T 细胞功能和分化的相关影响，以及 3) 表征负调节因子过表达的治疗潜力 使用 T 细胞介导的自身免疫性疾病模型的 DC。公共健康相关性：该项目将利用树突状细胞（DC）的专业抗原呈递特性和T细胞阻遏受体（负调节因子）的强大抑制信号相结合，以实现调节T细胞功能和诱导抗原特异性T细胞低反应性和耐受性的目标。这将通过外源性过表达具有 T 细胞阻遏受体（CTLA-4、PD-1 和 BTLA）特异性配体的 DC 并加载感兴趣的抗原来主动抑制 T 细胞，同时在抗原呈递过程中传递抑制信号来实现。通过产生适应性低反应性和调节性 T 细胞来诱导抗原特异性 T 细胞耐受将是治疗自身免疫和移植物排斥的最有效方法，我们相信，我们提出的方法将是实现该目标的最有效方法之一。此外，这种方法将是研究抗原呈递过程中 T 细胞阻遏受体结合增强效果的有效方法之一。我们的研究将对治疗自身免疫的方法产生巨大影响，而无需冒机会性感染的风险，并且无需使用一般免疫抑制剂进行终生治疗。