Engineering and targeting novel antigen-specific tolerogenic interfaces

工程设计和靶向新型抗原特异性耐受性界面

基本信息

批准号：
9118059
负责人：
Remi J Creusot
金额：
$ 20万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118059
关键词：
Adverse effects Affect Allergic Animal Model Animals Antigen-Presenting Cells Antigens Apoptosis Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Automobile Driving Biological Biology Bone Marrow CD4 Positive T Lymphocytes Cell Therapy Cells Charge Clinical Trials Complex Dendritic Cells Development Disease Drug Combinations Electroporation Engineering Environmental Risk Factor Exploratory/Developmental Grant Genes Genetic Goals Health Heterogeneity Homing Human Immature Bone Immune Immune Tolerance Immunotherapy In Vitro Incidence Individual Insulin-Dependent Diabetes Mellitus Interleukin-10 Islets of Langerhans Life Lymphoid Tissue Maintenance Malignant Neoplasms Mediating Messenger RNA Methods Modification Mus Outcome Pancreas Pathway interactions Pattern Pharmaceutical Preparations Phenotype Population Regulatory T-Lymphocyte Research Safety Signal Pathway Signal Transduction Site Specificity Stromal Cells Sum Surface System T-Lymphocyte Testing Tissues anergy autoreactive T cell base cellular engineering combinatorial design diabetogenic human disease improved in vivo interest islet lymph nodes migration novel overexpression pre-clinical receptor response success targeted treatment tool

项目摘要

DESCRIPTION (provided by applicant): Autoimmune diseases are the result of impaired immune tolerance and animal studies indicate that restoring antigen-specific tolerance permanently can constitute a cure. However, this is very challenging to achieve in humans, because they are highly heterogeneous in their genetic and environmental makeup, and the diseases multifactorial. Meanwhile, the incidence of these diseases is on the rise. This heterogeneity may be overcome by targeting multiple biological pathways of tolerance induction, specifically in disease-driving self-reactive T cells, and possibly within strategic tissue sites. Various combinations of drugs, biologics and/or tolerizing antigens have been tested in therapy, but each component acts independently in this case. What is missing is a single "tolerogenic interface" that enables the antigenic and multiple tolerogenic signals to act together and concomitantly on target T cells, resulting in optimal signal integration, and ultimately, optimal reprograming of these self-reactive T cells. The most clinically beneficial outcome is the reprograming into antigen-specific regulatory T cells (Tregs), which are long-lived and have the ability to perpetuate tolerance by suppressing autoimmune responses to other disease-relevant antigens (infectious tolerance). Dendritic cells (DCs), already tested in the treatment of a variet of human diseases, are among the most versatile antigen-presenting cells that can be manipulated for this purpose. However, the creation of customized and complex interfaces consisting of relevant antigens and optimal combinations of tolerogenic signals has not yet been achieved. With this Exploratory/Developmental grant, we propose to engineer new DC-based tolerogenic interfaces whose components are delivered as mixtures of mRNA by electroporation. Under Specific Aim 1, we will test the expression of several antigens and tolerogenic products in this system, and identify combinations that can most efficiently reprogram diabetogenic T cells into Tregs. The major goals are to find signaling pathways that synergize in inducing highly functional and stable Tregs, and to generate Tregs in vivo that are capable of mediating long-lasting protection from disease. Under Specific Aim 2, we will use the same mRNA-based manipulation approach to overexpress specific homing receptors in DCs. The goal is to enhance the migration of tolerogenic DCs to the pancreatic lymph nodes, where diabetogenic T cells are primed, or to the pancreatic islets, where they exert their pathogenic function. DC-based cell therapies have been increasingly tested in clinical trials to treat human disease, mostly cancer, and more recently for autoimmunity. These studies suggest that DCs are devoid of the adverse effects of many drugs and biologics tested to date. The development of tolerogenic DCs that (1) target specific T cells, (2) engage them through multiple biological pathways for efficient reprograming into Tregs and (3) accumulate better and preferentially in relevant tissues will greatly improve both efficacy and safety of cell-based therapies for autoimmune diseases.

描述（由申请人提供）：自身免疫性疾病是免疫耐受受损的结果，动物研究表明永久恢复抗原特异性耐受可以构成治愈方法。然而，这在人类中实现是非常具有挑战性的，因为它们具有高度异质性。同时，这些疾病的发病率正在上升，可以通过针对耐受诱导的多种生物途径来克服，特别是在疾病驱动的自身反应性 T 细胞中，也可能是在其内部。药物、生物制剂和/或耐受性抗原的各种组合已在治疗中进行了测试，但在这种情况下，每种成分都独立起作用，缺少的是使抗原和多种耐受性信号发挥作用的单一“耐受性界面”。一起并同时作用于靶 T 细胞，从而实现最佳信号整合，并最终对这些自身反应性 T 细胞进行最佳重编程，临床上最有益的结果是重编程为抗原特异性调节 T 细胞。树突状细胞 (Treg) 寿命较长，能够通过抑制对其他疾病相关抗原的自身免疫反应（感染性耐受）来维持耐受性，已在多种人类疾病的治疗中进行了测试。然而，由相关抗原和耐受信号的最佳组合组成的定制和复杂界面的创建尚未实现。在这项探索性/开发资助中，我们建议设计新的基于 DC 的耐受性界面，其成分通过电穿孔作为 mRNA 混合物传递，在特定目标 1 下，我们将测试该系统中几种抗原和耐受性产物的表达，并确定组合。主要目标是找到协同诱导高功能且稳定的 Tregs 的信号通路，并在体内产生能够介导的 Tregs。在特定目标 2 下，我们将使用相同的基于 mRNA 的操作方法来过度表达 DC 中的特定归巢受体，目标是增强耐受性 DC 向胰腺淋巴结的迁移，其中导致糖尿病的 T 细胞。这些研究表明，基于 DC 的细胞疗法已在治疗人类疾病（主要是癌症）和最近的自身免疫性疾病中进行了越来越多的测试。 DCs 没有迄今为止测试的许多药物和生物制剂的副作用。耐受性 DCs 的开发能够 (1) 靶向特定的 T 细胞，(2) 通过多种生物途径使它们有效地重新编程为 Tregs，以及 (3) 更好地积累。并优先在相关组织中进行，将大大提高自身免疫性疾病细胞疗法的疗效和安全性。