Harnessing monoclonal Treg for the treatment of autoimmune uveitis

利用单克隆 Treg 治疗自身免疫性葡萄膜炎

基本信息

批准号：
9045643
负责人：
Johannes Nowatzky
金额：
$ 18.14万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9045643
关键词：
Adoptive Transfer Adverse drug effect Adverse effects Affect American Animal Model Antigens Arrestins Autoimmune Diseases Autoimmunity Autologous Basic Science Biology Cells Cellular Immunology Clinical Cloning Dendritic Cells Development Disease Epitopes Eragrostis Eye Eye diseases Gene Transfer Goals Health Human Immunization Immunology Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Impairment In Vitro Inflammation Inflammatory Insertional Mutagenesis Insulin-Dependent Diabetes Mellitus Knowledge LRRC32 gene Maintenance Mediating Mentors Methodology Methods Modality Modeling Multiple Sclerosis Mus Mutagenesis Pathogenicity Pathology Patients Peripheral Blood Mononuclear Cell Phenotype Physicians Preclinical Testing Preparation Proteins Qualifying Reapplication Regulatory T-Lymphocyte Research Research Personnel Rheumatoid Arthritis Rheumatology Risk Scientist Self Tolerance Site Specificity Staging System T cell response T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte Tail Techniques Testing Therapeutic Translations United States United States National Institutes of Health Up-Regulation Ursidae Family Uveitis Validation Viral Vision Wit Work autoimmune uveitis base career cell type clinical practice cohort effective therapy experience graft vs host disease humanized mouse improved in vivo interstitial retinol-binding protein mouse model novel novel strategies prevent prototype receptor expression reconstitution response skills targeted treatment

项目摘要

DESCRIPTION (provided by applicant): The main objective of this application is to provide the PI with research experience and skills which will enable him to function as an independent investigator in the field of cell-based immunotherapy development at the interface between rheumatology and ocular immunology. To this end, the candidate has assembled a mentoring team which includes internationally-recognized leaders in the fields of regulatory T cell (Treg) biology (Juan Lafaille, NYU), rheumatology (Steven Abramson, NYU), and ocular immunology (Rachel Caspi, NIH-NEI). The overarching career goal of the applicant is to develop into a highly qualified physician-scientist with strong basic science skills AND the capacity for rapid translation of immunology concepts to aspects of clinical practice, especially as pertains to the development of new cell-based immunotherapeutic modalities. The proposed project is tailored to these goals through the incorporation and step-wise extension of expertise already acquired by the applicant in clinical and experimental aspects of Behcet's eye disease, and cellular immunology, to new applications, methods and concepts, i.e., experimentation with humanized animal models of inflammatory disease for in vivo proof-of-principle and mechanistic studies. In particular, the project investigates the possibility of massive ex vivo expansion and subsequent adoptive transfer (reinjection therapy) of human regulatory T cell clones for the control of pathogenic effector T cell (Teff) responses in autoimmune uveitis. It tests the main hypothesis that human Treg of the CD4+/CD25hi/CD127lo/Foxp3+/Helios+ phenotype [thymic, or natural (n)Treg] maintain functional stability in vitro and in vivo following massive monoclonal ex vivo expansion, and effectively control general and/or target (uveitis) antigen-related effector T cell responses. The applicant has shown that cloning and massive monoclonal expansion of nTreg under maintenance of in vitro suppressor function is possible, and he now proposes to solidify this approach in Specific Aim 1 and contrast its efficacy with polyclonal, existing approaches. Specific Aim 2 tests the hypothesis that nTreg can be cloned with knowledge of their antigen-specificity. He will use the skills acquired in his previous mentored work in dendritic cell-mediated T cell priming and expansion and incorporate uveitis antigen-specific aspects of immunodominance and pathogenicity as the main educational and scientific objective. Specific Aim 3 focuses on in vivo validation and testing of monoclonally expanded Treg in a 2-tailed approach: Subaim a) will test general immunosuppressive function of clones with unselected antigen-specificity the PI has already generated, in a humanized mouse model of graft-versus-host-disease (GVHD) to determine and quantify in vivo suppression, and subaim b) will establish a humanized experimental autoimmune uveitis (EAU) mouse model for preclinical testing of nTreg clones with uveitis antigen specificity. The knowledge to be gained from the proposed studies bears the potential to significantly improve current approaches of Treg expansion and adoptive transfer strategies, which at present rely mostly on polyclonal techniques and are limited by the unwanted co-expansion of potentially harmful Teff, unstable suppressor function and low expansion rates. The antigen-specific cloning approach further bears the potential of targeted suppression of Teff responses at the site of pathology without significant systemic immunosuppression and eliminates the risks of insertional mutagenesis and dual T cell receptor (TCR) expression inherent in the currently prevailing strategies that confer antigen specificity through lentiviral TCR transduction into polyclonally expanded Treg. Apart from the potential of a new modality of targeted treatment for autoimmune uveitis, results of this research are likely to have a high degree of generalizability to other forms of autoimmune diseases.

描述（由应用程序提供）：本应用程序的主要目的是为PI提供研究经验和技能，这将使他能够在风湿病学和眼部免疫学之间的界面上充当基于细胞的免疫疗法开发领域的独立研究者。为此，候选人组建了一个心理团队，其中包括在监管T细胞（Treg）生物学领域（Juan Lafaille，NYU），风湿病学（Steven Abramson，Nyu）和Ocular Immunology（Rachel Caspi，Nih-Nih-Nei）的领域。该应用程序的总体职业目标是发展成具有强大基础科学技能的高素质的物理科学家，以及将免疫学概念快速转化为临床实践方面的能力，尤其是与新的基于细胞的免疫治疗方式的发展有关。拟议的项目是通过该应用程序在Behcet眼科临床和实验方面获得的专业知识的保险和逐步扩展来量身定制的。特别是，该项目研究了人类调节性T细胞克隆的大规模外体扩张和随后的自适应转移（重新注射疗法）的可能性，以控制自身免疫性葡萄膜炎中病原效应T细胞（TEFF）反应。 It tests the main hypothesis that human Treg of the CD4+/CD25hi/CD127lo/Foxp3+/Helios+ phenotype [thymic, or natural (n)Treg] maintain functional stability in vitro and in vivo following massive monoclonal ex vivo expansion, and effectively control general and/or target (uveitis) antigen-related Effector T cell responses.申请人表明，在维护体外抑制器功能下，NTREG的克隆和大量的单克隆扩张是可能的，他现在建议在特定目标1中固化这种方法，并将其与多克隆的现有方法对比。特定的目标2检验了可以通过了解其抗原特异性克隆NTREG的假设。他将利用他以前在树突状细胞介导的T细胞启动和扩张中的Mendored工作中获得的技能，并纳入了免疫主持和致病性的葡萄膜炎抗原特异性方面，作为主要的教育和科学目标。 Specific Aim 3 focuses on in vivo validation and testing of monoclonally expanded Treg in a 2-tailed approach: Subaim a) will test general immunosuppressive function of clones with unselected antigen-specificity the PI has already generated, in a humanized mouse model of Graft-versus-host-disease (GVHD) to determine and quantify in vivo suppression, and subaim b) will establish a humanized experimental自身免疫性葡萄膜炎（EAU）小鼠模型，用于具有葡萄膜炎抗原特异性的NTREG克隆的临床前测试。从提出的研究中获得的知识具有显着改善Treg扩展和适应性转移策略的当前方法的潜力，这些策略主要依赖于多克隆技术，并且受可能有害的TEFF，不稳定的抑制器功能和低扩展率的不必要的共同扩展而受到限制。抗原特异性克隆方法进一步具有靶向抑制TEFF反应在病理部位的潜力，而没有明显的全身免疫抑制，并消除了当前策略中固有的插入性诱变和双T细胞受体（TCR）表达固有的风险，这些策略可通过将抗原特异性通过lentivir trydcr延伸到抗精神特异性中。除了对自身免疫性葡萄膜炎有针对性治疗的新方法的潜力外，这项研究的结果可能对其他形式的自身免疫性疾病具有高度的普遍性。