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: 7655015
• 负责人: CHENTHAMARAKSHAN VASU
• 金额: $ 39.25万
• 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/7655015
• 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; 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; Reporting; Rest; Risk; Role; Safety; Signal Transduction; Specificity; Staging; Stem cells; Surface; Synapses; System; 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)：共刺激通路被认为是T细胞激活和分化所必需的。在遇到抗原的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。共抑制物/抑制物受体(负调节因子)，在活化的T细胞上显著上调，并在过去几年成为治疗的靶点。抗原特异性耐受的诱导依赖于TCR和一个或多个阻遏受体的同时参与。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(Tregs)的诱导和/或扩增有关。抗原特异性Tregs可抑制效应性T细胞反应，为自身免疫提供长期持续的保护作用。我们的假设是，利用树突状细胞(DC)稳定地过表达负调控配体，阻遏受体和TCR在抗原特异性T细胞上的优势结合将诱导有效的、持久的抗原特异性T细胞耐受。到目前为止，我们的研究已经证明，通过DC导向的方法将抑制物受体结合到T细胞上，可以在体内外诱导抗原特异性T细胞反应的显着抑制和低增殖T细胞的产生，并具有产生大量抑制性细胞因子的能力，如IL-10和TGF-21。因此，采用稳定外源高表达T细胞抑制受体特异性配体B7.1wa、PD-L1和hvem-CRD1、CTLA-4、PD-1和BTLA的方法来产生耐受性APC。这些树突状细胞可以将抗原递呈给T细胞，同时以更强的强度与其阻遏受体结合。这些致耐受树突状细胞可以诱导抗原特异性T细胞和促炎细胞因子反应的显著抑制，但增强抗炎细胞因子反应。在这个系统中，DC的特殊抗原提呈特性与工程DC主要结合激活的T细胞上的抑制受体的能力被利用。这种负性调节配体过表达的DC也可以成为研究T细胞抑制受体在抗原提呈过程中增强结合的作用的有力工具。本研究的目的是：1)了解过度表达T细胞抑制受体配体的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T细胞抑制受体连接诱导信号增强的机制及其对效应T细胞功能和分化的相关影响；3)利用T细胞介导的自身免疫病模型表征过表达负调控因子的DC的治疗潜力。公共卫生相关性：该项目将利用树突状细胞(DC)的专业抗原提呈特性和T细胞抑制受体(负调节因子)强大的抑制信号相结合，实现调节T细胞功能和诱导抗原特异性T细胞低反应和耐受的目标。这将通过外源过度表达具有T细胞抑制受体特异性配体(CTLA-4、PD-1和BTLA)的DC，并将感兴趣的抗原(S)负载到DC上，通过在抗原提呈过程中传递抑制信号来主动抑制T细胞。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反应的最有效方法，我们相信，我们提出的方法将是实现这一目标的最有效方法之一。此外，这种方法将是研究T细胞抑制受体在抗原呈递过程中增强参与的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，而不存在机会性感染的风险，以及通过消除使用普通免疫抑制剂进行终身治疗的需要。