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

基本信息

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
项目类别：
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

项目摘要

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。在遇到的T细胞上操纵这些信号是诱导抗原特异性耐受性以预防和抑制自身免疫性的最有吸引力的方法。在激活的T细胞上显着上调的联合抑制剂/阻遏物受体（负调节剂），并且一直是关注分子作为过去几年的治疗靶标。抗原特异性耐受性的诱导取决于TCR的并发参与和其中一个或多个这些阻遏物受体。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T细胞（Tregs）的诱导和/或扩展有关。抗原特异性Treg可以抑制效应T细胞反应并提供长期持续保护免受自身免疫性的保护。我们的假设是，使用树突状细胞（DCS）（稳定过表达的负调节配体）在抗原特异性T细胞上的主要参与以及TCR将诱导有效的持久抗原特异性T细胞耐受性。到目前为止，我们的研究表明，通过DC有向方法在T细胞上对抗原特异性参与可能会诱导抗原特异性T细胞反应的显着抑制和产生抗原性T细胞的产生，并具有产生大量抑制细胞因子（例如IL-10和TGF-21）的能力。因此，对T细胞抑制剂受体特异的配体，B7.1WA，PD-L1和HVEM-CRD1的稳定外源性过表达的方法采用了CTLA-4，PD-1和BTLA用于产生耐受型APC。这些DC可以向T细胞呈现抗原，并以增强的强度同时吸收其阻遏物受体。这些耐受性DC可以诱导对抗原特异性T细胞和促炎性细胞因子反应的深刻抑制，但增强了抗炎性细胞因子反应。在该系统中利用了DC的非凡抗原呈现DC的特性，并结合了工程DC的主要使阻遏物受体接触的能力。这种负调节配体过表达的DC也可能是研究在抗原表现过程中提高T细胞阻遏物受体参与的效果的强大工具。这项研究将针对1）理解DC的潜力，而DC的可能过度表达的T细胞抑制剂受体诱导和维持抗原特异性T细胞低反应性和容忍度，2）理解增强T细胞抑制剂 - 抑制剂 - 抑制剂诱导的信号和相关效应的效应和3个效应的效应的机制，以及对效应的效应，以及对效应的效应，并表现出3）表现的3）。 DC使用T细胞介导的自身免疫性疾病模型。公共卫生相关性：该项目将利用树突状细胞（DCS）的专业抗原表现特性以及T细胞阻遏物受体受体（负调节剂）的强大抑制信号，以实现调节T细胞功能并诱导抗原T特异性T细胞性抗原抗抑制作用和容忍度的目标。这将通过外源表达DC，该DC具有特异性的配体，该配体特异于T细胞抑制剂受体（CTLA-4，PD-1和BTLA），并加载它们在抗原呈递过程中带来抑制性信号的主动抑制T细胞的抗原（S）。通过产生适应性的低反应性和调节性T细胞来诱导抗原特异性T细胞的耐受性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，这种方法将是研究在抗原表现过程中T细胞阻遏受体增强参与效果的有效方法之一。我们的研究将对治疗自身免疫性的方法产生巨大影响，而无需冒险感染，以及消除使用普通免疫抑制剂进行终身治疗的需求。