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Engineering CAR Tregs for type 1 diabetes

工程 CAR Tregs 治疗 1 型糖尿病

基本信息

批准号：
10495238
负责人：
Brian T Fife
金额：
$ 23.15万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495238
关键词：
Adoptive Transfer Affect Animal Model Antibodies Antibody Affinity Antigen Targeting Antigens Autoantigens Autoimmunity Beta Cell CD8-Positive T-Lymphocytes Cell Fraction Cell Surface Proteins Cell Survival Cell physiology Cell surface Cells Clinical Research Diabetes Mellitus Disease Progression Engineering Funding Goals Grant Human Hybrids Immune Immune Tolerance Immune response Immunosuppression Immunotherapy In Vitro Inbred NOD Mice Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Lead Mediating Methods Modeling Monoclonal Antibodies Mus Pancreas Patients Peptide/MHC Complex Peptides Pre-Clinical Model Prevention Proteins Reagent Regulatory T-Lymphocyte Research Risk Safety Series Signal Transduction Specificity Splenocyte T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Tissues Transgenic Organisms Translations Treg therapy Work antigen binding autoreactivity chimeric antigen receptor diabetic diabetogenic draining lymph node experimental study extracellular high reward high risk in vivo islet lymph nodes model development preservation prevent restoration success

项目摘要

Summary Type 1 diabetes (T1D) results from a breakdown in immunological tolerance and the resulting T cell- mediated destruction of insulin producing beta cells in the pancreas. This is caused by defective “regulatory” T cells (or Tregs), which normally suppress harmful immune responses. In T1D, Tregs stop protecting beta cells. Work from T1D animal models has shown that therapeutic restoration of Tregs can prevent disease progression, and clinical studies have shown the safety of this approach in humans. Despite this initial success, there are significant hurdles for long term and global Treg therapy in T1D. Current methods infuse large numbers of polyclonal Tregs that have not been selected for antigen specificity, so they carry the risk of non-specific immunosuppression. Furthermore, it is difficult to expand enough of these polyclonal Tregs required for therapy, and even then, only a small fraction of the cells actually suppress autoimmunity. These challenges can be solved by creating “designer” Tregs that are engineered for specificity and have the best chance of resetting immune tolerance. If successful, this technology would lead to a more personalized and effective T1D immunotherapy. We recently developed an approach to engineer antigen-specific Tregs by re-directing their specificity using chimeric antigen receptors, or CARs. In this application, we will test if peptide specific MHC-CAR-Tregs prevent and/or reverse T1D in NOD mice. We hypothesize that mouse Tregs expressing a hybrid insulin peptide-MHCII- specific CAR will prevent T1D by restoring immune tolerance and suppressing autoreactive effector CD4+ and CD8+ T cell function to limit their accumulation in the pancreas.

概括 1 型糖尿病 (T1D) 是由于免疫耐受性崩溃以及由此产生的 T 细胞- 介导对胰腺中产生胰岛素的β细胞的破坏。这是由于缺陷造成的 “调节性”T 细胞（或 Tregs），通常会抑制有害的免疫反应。在 T1D 中，Treg 停止保护β细胞。 T1D 动物模型的研究表明，治疗性恢复 Tregs 可以预防疾病进展，临床研究表明这种方法对人类是安全的。尽管取得了初步成功，但 T1D 的长期和全球性 Treg 治疗仍存在重大障碍。目前的方法注入大量尚未选择抗原的多克隆 Tregs 特异性，因此它们具有非特异性免疫抑制的风险。此外，扩展也很困难治疗所需的这些多克隆 Tregs 数量足够多，即便如此，也只需要一小部分细胞实际上抑制自身免疫。这些挑战可以通过创建“设计者”Treg 来解决，专为特异性而设计，并且最有可能重置免疫耐受性。如果成功的话，这技术将带来更加个性化和有效的 T1D 免疫疗法。我们最近开发了一种通过使用嵌合抗原重新定向其特异性来改造抗原特异性 Tregs 的方法受体，或 CAR。在此应用中，我们将测试肽特异性 MHC-CAR-Treg 是否可以预防和/或逆转 NOD 小鼠的 T1D。我们假设小鼠 Tregs 表达混合胰岛素肽-MHCII- 特定的 CAR 将通过恢复免疫耐受和抑制自身反应效应子 CD4+ 来预防 T1D CD8+ T 细胞的功能是限制其在胰腺中的积累。