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: 8015582
• 负责人: CHENTHAMARAKSHAN VASU
• 金额: $ 3.5万
• 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 2011-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015582
• 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 Differentiation process; Cell physiology; Cells; Characteristics; Clinical; Complementary DNA; Complex; Cytotoxic T-Lymphocyte-Associated Protein 4; Dendritic Cells; Disease; Disease model; Down-Regulation; Effectiveness; Engineering; Event; 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; Light; 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 Mice; Wild Type Mouse; cellular engineering; cost effective; 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（由申请方提供）：共刺激通路被认为是T细胞活化和分化所必需的。在抗原接触的T细胞上操纵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。在活化的T细胞上显著上调的共抑制剂/阻遏物受体（负调节剂），并且在过去几年中作为治疗靶点一直是关注的分子。抗原特异性耐受的诱导依赖于TCR和这些阻遏物受体中的一种或多种的同时接合。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（Tcells）的诱导和/或扩增有关。抗原特异性T细胞因子可以抑制效应T细胞应答，并提供长期持续的自身免疫保护。我们的假设是，使用经工程化以稳定过表达负调节配体的树突状细胞（DC），阻遏物受体沿着与抗原特异性T细胞上的TCR的显性接合将诱导有效的持久的抗原特异性T细胞耐受。迄今为止，我们的研究已经证明，通过DC定向方法对T细胞上的阻遏物受体的抗原特异性接合可以诱导抗原特异性T细胞应答的显著抑制和具有在体外和体内产生大量抑制性细胞因子如IL-10和TGF-21的能力的低增殖性T细胞的产生。因此，采用对T细胞阻遏物受体CTLA-4、PD-1和BTLA特异性的配体B7.1wa、PD-L1和HVEM-CRD 1的稳定外源性过表达的方法来产生致耐受性APC。这些DC可以将抗原呈递给T细胞，同时以增强的强度接合它们的阻遏物受体。这些致耐受性DC可诱导抗原特异性T细胞和促炎细胞因子应答的深度抑制，但增强抗炎细胞因子应答。在该系统中利用了DC的特殊抗原呈递特性与工程化DC主要接合活化T细胞上的阻遏物受体的能力的组合。这种负调节配体过表达的DC也可以是研究在抗原呈递期间T细胞阻遏物-受体的增强接合的作用的有力工具。本研究的目的是1）理解过表达T细胞阻遏物-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）理解增强的T细胞阻遏物-受体连接诱导的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，和3）使用T细胞介导的自身免疫疾病模型表征负调节因子过表达DC的治疗潜力。公共卫生相关性：本项目将利用树突状细胞（DCs）的抗原提呈特性和T细胞抑制受体（负调节因子）的强大抑制信号，共同调控T细胞功能，诱导抗原特异性T细胞低反应性和耐受性。这将通过外源性过表达具有T细胞阻遏物受体（CTLA-4、PD-1和BTLA）特异性配体的DC并将它们负载有感兴趣的抗原以通过在抗原呈递期间递送抑制信号来主动抑制T细胞来实现。通过产生适应性低应答和调节性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，这种方法将是一种有效的方法来研究增强的参与T细胞抑制受体在抗原呈递过程中的影响。我们的研究将对治疗自身免疫的方法产生巨大影响，而不会有机会性感染的风险，以及消除使用一般免疫抑制剂进行终身治疗的需要。