Defining the induction and maintenance of myelin-specific tolerance in T cells and B cells using local lymph node depots

使用局部淋巴结库定义 T 细胞和 B 细胞中髓磷脂特异性耐受的诱导和维持

• 批准号: 10557140
• 负责人: Christopher M Jewell
• 金额: $ 55.47万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557140
• 关键词: Address; Adopted; Adoptive Transfer; Aftercare; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biocompatible Materials; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Central Nervous System; Chronic; Clinical; Cues; Data; Deposition; Diffusion; Disease; Distant; Engineering; Environment; Equilibrium; Experimental Autoimmune Encephalomyelitis; Face; Family; Goals; Health Care Costs; Histology; Human; Humira; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunocompromised Host; Immunologics; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Inflammation; Inflammatory; Infusion procedures; Injections; Interleukin-10; Kinetics; Knockout Mice; Knowledge; Link; Magnetic Resonance Imaging; Maintenance; Memory; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Mus; Myelin; Nanotechnology; Nature; Nerve Degeneration; Nervous System Physiology; Paralysed; Pathogenicity; Patients; Peptides; Pharmaceutical Preparations; Play; Polymers; Population; Pre-Clinical Model; Preclinical Testing; Process; Production; Regulatory T-Lymphocyte; Reporter; Rest; Route; Signal Transduction; Sirolimus; Site; Societies; Specificity; Structure; Structure of germinal center of lymph node; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Transgenic Organisms; Vaccines; Vision; Work; biodegradable polymer; combat; controlled release; cytokine; design; draining lymph node; efficacy testing; immune function; immunoengineering; immunoregulation; injection/infusion; lymph node microenvironment; lymph nodes; migration; multiple sclerosis treatment; nanoparticle; neuroinflammation; novel therapeutics; particle; polarized cell; preclinical study; prevent; programs; remyelination; response; side effect; therapeutic target; transdifferentiation

PROJECT SUMMARY: During autoimmunity, the body incorrectly identifies “self” molecules as foreign. In multiple sclerosis (MS) attack of myelin in the central nervous system (CNS) leads to neurodegeneration. Existing therapies for MS range from immunosuppressants to newer monoclonal antibodies, but even the latter do not distinguish between healthy and self-reactive cells displaying the antibody target. Thus, while beneficial, existing therapies are not curative, cause immunocompromising side effects, and require life-long compliance. These limitations have motivated efforts to control autoimmunity with vaccine-like specificity, leaving the rest of the immune system intact. One such antigen-specific tolerance strategy being studied pre-clinically and in human trials is co-delivery of myelin peptide and tolerizing immune signals to promote populations, such as regulatory T cells (TREG) that combat MS. The polarization of T cells into inflammatory T cells (e.g., TH17) or TREG is localized to lymph nodes (LNs), tissues that coordinate immunity. New studies also reveal TREG can adopt memory functions to maintain tolerance. Further, in appropriate tissue niches, inflammatory TH17 cells can transdifferentiate to TREG. Likewise, B cells are relevant to MS in several ways, including producing pathogenic myelin-specific antibodies, and as therapeutic targets able to adopt regulatory function. LNs play key roles in these processes, directing dynamic stromal organization to promote and regulate cell interaction and modulatory cues that control T and B cell polarization between (auto)inflammatory and tolerance functions. From a therapeutic view, controlling this niche is challenging using conventional delivery technologies (e.g., systemic injections/infusions), and even biomaterial approaches such as targeted nanoparticles face difficulty establishing durable tissue environments after injection. However, the ability to understand and control the integration of signals in the LN microenvironment could enable potent, myelin-specific immunotherapies that avoid immunosuppression. We propose tackling this goal using a platform that combines direct intra-LN (i.LN.) injection with controlled release biomaterial depots. We have shown diffusion-restricted polymer depots that are too large to drain from LNs after injection concentrate and retain depot-loaded cargo in LNs. Using depots loaded with myelin peptide and rapamycin - an immunoregulatory drug, we have shown a single treatment at the peak of disease in a pre-clinical model of MS reverses paralysis for over 90 days. Efficacy is not achieved with i.LN. injection of soluble cargo, or during injection of depots via traditional routes. We will use this interdisciplinary immune engineering approach to understand how local controlled release promotes a tolerogenic stromal LN environment and how these effects induce and maintain long-lasting tolerizing function against myelin in T and B cells. The aims are 1) Define the robustness of efficacy and the underpinning therapeutic effects on neuroinflammation, 2) Show the durability of tolerance is antigen-dependent and driven by TREG maintenance & plasticity, 3) Show i.LN. depots disrupt germinal centers, reduce auto-antibodies, & induce tolerogenic B cells.

项目概述：在自身免疫过程中，机体错误地将“自身”分子识别为外来分子。在