Harnessing biomaterials to study the link between local lymph node function and systemic tolerance

利用生物材料研究局部淋巴结功能与全身耐受性之间的联系

• 批准号: 10449748
• 负责人: Christopher M Jewell
• 金额: $ 15.45万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449748
• 关键词: Address; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Biocompatible Materials; Cell physiology; Chronic; Clinical Trials; Cues; Data; Development; Disease; Distal; Distant; Dose; Encapsulated; Experimental Autoimmune Encephalomyelitis; Goals; Immune; Immune Tolerance; Immune response; Immune signaling; Immune system; Immunocompromised Host; Immunosuppression; Individual; Inflammatory; Inflammatory Response; Injections; Insulin-Dependent Diabetes Mellitus; Kinetics; Knowledge; Link; Location; Lupus; Lymph Node Tissue; Modeling; Multiple Sclerosis; Mus; Myelin; Nature; Neuraxis; Neurodegenerative Disorders; Paralysed; Patients; Peptides; Pharmaceutical Preparations; Play; Regulatory T-Lymphocyte; Reporting; Rest; Rheumatoid Arthritis; Role; Route; Signal Transduction; Sirolimus; Site; Specificity; Spleen; Structure; System; T-Lymphocyte; Testing; Tissues; Vaccines; Work; adaptive immunity; combat; controlled release; conventional therapy; design; disorder control; insight; interest; lymph nodes; novel therapeutics; polarized cell; pre-clinical; prevent; programs; theories; tool

PROJECT SUMMARY During autoimmune disease, the body incorrectly identifies “self” molecules as foreign and mounts a chronic immune attack. Conventional therapies employ broad immunosuppression, which has provided significant benefits to patients, but can leave these individuals immunocompromised. This limitation, along with the lack of cures for most autoimmune diseases, has sparked intense interest in strategies that could control autoimmunity with vaccine-like specificity, leaving the rest of the immune system intact. Several pre-clinical reports and clinical trials have investigated this theory to combat multiple sclerosis (MS), a neurodegenerative disease in which myelin in the central nervous system (CNS) is attacked by the immune system. An important finding from these studies is that co-administration of myelin peptide and tolerizing immune signals can promote the development of regulatory T cells (TREGS) that ameliorate disease. The polarization of naïve T cells into inflammatory T cells (e.g., TH17) or TREGS is localized to lymph nodes (LNs), the tissues that coordinate adaptive immunity. However, the link between the combinations, concentrations and persistence of immune cues in LNs, and the extent and specificity of systemic tolerance elicited, is not well understood. New knowledge of how signal integration in LNs drives tolerance could help address limitations associated with current therapies, such as incomplete control of disease and non-specific suppression. This proposal will study these fundamental questions in disease using a new platform that combines direct intra-LN (i.LN.) injection with controlled release biomaterial depots. Preliminary data in mice demonstrate that a single dose of depots co-encapsulating two of the most studied signals – myelin peptide and rapamycin, a drug known to promote TREGS – permanently reverses disease-induced paralysis in a model of MS (EAE). These effects occur even when depots are administered at the peak of disease, confirming the power of this system to serve as a tool to locally control the function of one LN, while dissecting the impact on systemic tolerance and at distant sites such as the CNS, spleen, and distal LNs. We hypothesize that this platform will allow previously inaccessible questions to be addressed, including the roles that local signals, combinations, and kinetics within LNs play in programming the nature of tolerance. The specific aims are 1) determine how local signals in LNs polarize T cell function and program systemic tolerance, 2) decipher the impact of signal location, delivery route, and kinetics on T cell polarization, 3) compare the local structure and function of depot-treated LNs to distal LNs, spleen, and CNS, and 4) test if the link between local function and systemic tolerance is generalizable to other self-antigens. This work will generate insight that informs design of new therapies that aim to promote tolerogenic function in an antigen-specific manner during autoimmune diseases such as MS, Type 1 diabetes, and rheumatoid arthritis.

项目总结

项目成果

Tissue-Targeted Drug Delivery Strategies to Promote Antigen-Specific Immune Tolerance.

促进抗原特异性免疫耐受的组织靶向药物递送策略。

• DOI: 10.1002/adhm.202202238
• 发表时间: 2023
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Rui,Yuan;Eppler,HaleighB;Yanes,AlexisA;Jewell,ChristopherM
• 通讯作者: Jewell,ChristopherM

Directing toll-like receptor signaling in macrophages to enhance tumor immunotherapy.

• DOI: 10.1016/j.copbio.2019.01.010
• 发表时间: 2019-12
• 期刊: Current opinion in biotechnology
• 影响因子: 7.7
• 作者: Qin Zeng;C. Jewell

Biomaterial-enabled induction of pancreatic-specific regulatory T cells through distinct signal transduction pathways.

• DOI: 10.1007/s13346-021-01075-5
• 发表时间: 2021-12
• 期刊: Drug delivery and translational research
• 影响因子: 5.4
• 作者: Carey ST;Gammon JM;Jewell CM
• 通讯作者: Jewell CM

Self-Assembly as a Molecular Strategy to Improve Immunotherapy.

• DOI: 10.1021/acs.accounts.0c00438
• 发表时间: 2020-11-17
• 期刊: Accounts of chemical research
• 影响因子: 18.3
• 作者: Froimchuk E;Carey ST;Edwards C;Jewell CM
• 通讯作者: Jewell CM

Spatial delivery of immune cues to lymph nodes to define therapeutic outcomes in cancer vaccination.

• DOI: 10.1039/d2bm00403h
• 发表时间: 2022-08-09
• 期刊: BIOMATERIALS SCIENCE
• 影响因子: 6.6
• 作者: Andorko, James, I;Tsai, Shannon J.;Gammon, Joshua M.;Carey, Sean T.;Zeng, Xiangbin;Gosselin, Emily A.;Edwards, Camilla;Shah, Shrey A.;Hess, Krystina L.;Jewell, Christopher M.
• 通讯作者: Jewell, Christopher M.