Treating T cell immunodeficiency among older adults by a recombinant Foxn1 fusion protein

重组 Foxn1 融合蛋白治疗老年人 T 细胞免疫缺陷

• 批准号: 10195564
• 负责人: Laijun Lai
• 金额: $ 24.15万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195564
• 关键词: Address; Adult; Age Factors; Aging; Amino Acids; Antibodies; Antigens; Architecture; Atrophic; Autoantigens; Autoimmune Diseases; Autoimmunity; Blood Proteins; Cell Count; Cell Nucleus; Cell physiology; Cell surface; Cells; Chimeric Proteins; Chronic Disease; Complementary DNA; Cytoplasm; Development; Dose; Drug Kinetics; Elderly; Family; Generations; Genetic; Genetic Transcription; Goals; HIV; Health; Human; Immune Tolerance; Immune response; Immune system; Immunity; Immunofluorescence Immunologic; In Vitro; Infection; Injections; Insertional Mutagenesis; Intramuscular; Intravenous; Lead; Longevity; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Medicine; Modernization; Modification; Mus; Natural regeneration; Organ; Outcome; Output; Patients; Peptides; Peripheral; Phase; Plasmids; Play; Predisposition; Prevention; Process; Proteins; Recombinants; Regimen; Risk; Rodent; Role; Route; System; T-Cell Development; T-Cell Immunodeficiency; T-Lymphocyte; T-cell receptor repertoire; Thymic epithelial cell; Thymus Gland; Time; Toxicology; Trans-Activators; Transgenes; Vaccination; Western Blotting; Winged Helix; age related; aged; autoreactive T cell; care outcomes; expression vector; fetal; gene cloning; improved; in vivo; influenza infection; member; mortality; novel; novel strategies; overexpression; peripheral lymphoid organ; postnatal; prevent; receptor; restoration; subcutaneous; thymocyte; transcription factor

Project Summary With modern advances in medicine, our average lifespan is increasing. However, advanced age is often accompanied by chronic diseases Our immune systems frequently plays a central role in the development of chronic diseases and T cells play a critical role in the immune system, providing protection against infection and cancer. The thymus, the primary organ for T cell development, however, undergoes a profound age-dependent atrophy, a process called thymic involution. Thymic involution results in T cell immunodeficiency, leading to increased susceptibility to infection and cancer, and difficulty in establishing protective immunity via vaccinations. Currently, there is no effective way to prevent or reverse T cell immunodeficiency among older adults. T cell development in the thymus is dependent on the thymic microenvironment, in which thymic epithelial cells (TECs) are the major components. However, TECs undergo qualitative and quantitative loss that is the major factor responsible for thymic atrophy. FOXN1 is a pivotal regulator for TEC development and maintenance, and we have shown that recombinant (r) FOXN1 fusion protein that contains FOXN1 and a protein transduction domain (PTD) can translocate from the cell surface into the cytoplasm and nucleus. Intrathymic (i.t.) injection of the rFOXN1 fusion protein into mice increases the number of TECs, and, consequently, enhances thymopoiesis and increases the number of T cells in the periphery. However, the i.t. injection route is impracticable for human application. Development of a more practicable regimen in term of the route of administration is necessary. The goal of this proposal is to develop new rFOXN1 fusion proteins that can migrate into the thymus to enhance thymopoiesis after intravenous (i.v.), intramuscular (i.m.), or subcutaneous (s.c.) injection into old mice. In the R21 phase, we will produce rFOXN1 fusion proteins containing FOXN1-PTD and thymus targeted peptides, or thymus/TEC specific receptor or antibody (Aim 1). We will then determine the ability of the rFOXN1 fusion proteins to migrate into the thymus when injected i.v., i.m. or s.c. (Aim 2), and to increase the number of TECs and T cells in old mice (Aim 3). If the R21 milestones are met, the R33 phase will be undertaken. Aim 4 will further characterize the thymus and the peripheral T cell function in the rFOXN1 fusion protein-treated old mice. In Aim 5, we will determine whether T cells in rFOXN1 fusion protein-treated old mice are immune tolerant to self-antigens to prevent autoimmunity. Aim 6 will analyze rodent toxicology and pharmacokinetics of a lead rFOXN1 fusion protein. Our long-term goal is to use the lead rFOXN1 fusion protein to prevent and treat T cell immunodeficiency in older adults, thus leading to improved healthcare outcomes and mortality rates.

项目摘要 随着现代医学的进步，我们的平均寿命正在增加。然而，高龄是 我们的免疫系统经常在免疫系统中发挥核心作用， 慢性疾病的发展和T细胞在免疫系统中发挥关键作用，提供保护 对抗感染和癌症然而，胸腺，T细胞发育的主要器官， 严重的年龄依赖性萎缩，这一过程被称为胸腺退化。胸腺退化导致T细胞 免疫缺陷，导致感染和癌症的易感性增加，以及难以建立 通过接种疫苗获得保护性免疫。目前，还没有有效的方法来阻止或逆转T细胞 老年人的免疫缺陷胸腺中的T细胞发育依赖于胸腺的 微环境，其中胸腺上皮细胞（TEC）是主要成分。然而，TEC经历了 这是导致胸腺萎缩的主要因素。 FOXN 1是TEC开发和维护的关键调节器，我们已经证明， 含有FOXN 1和蛋白转导结构域（PTD）的重组（r）FOXN 1融合蛋白可 从细胞表面转移到细胞质和细胞核中。胸腺内（i.t.）注射rFOXN 1 融合蛋白增加TEC的数量，因此，增强了胸腺生成， 增加外周T细胞的数量。然而，I.T.注射途径对人类是不可行 应用程序.有必要开发一种在给药途径方面更可行的方案。 该提案的目标是开发新的rFOXN 1融合蛋白，其可以迁移到胸腺中， 增强静脉内（i. v.）后的胸腺生成，肌内（i.m.），或皮下（s.c.）注射入老年人 小鼠在R21阶段，我们将制备含有FOXN 1-PTD和胸腺靶向的rFOXN 1融合蛋白， 肽或胸腺/TEC特异性受体或抗体（目的1）。然后我们将确定 静脉注射时rFOXN 1融合蛋白迁移到胸腺，I.M.或s.c. (Aim（2）、增加 老年小鼠中TEC和T细胞的数量（目的3）。如果R21里程碑得到满足，R33阶段将 进行。目的4将进一步表征rFOXN 1融合中的胸腺和外周T细胞功能 蛋白质治疗的老年小鼠。在目的5中，我们将确定rFOXN 1融合蛋白处理的老年小鼠中的T细胞是否 对自身抗原具有免疫耐受性以防止自身免疫。目标6将分析啮齿动物毒理学， 图10示出了先导rFOXN 1融合蛋白的药代动力学。我们的长期目标是使用前导rFOXN 1融合蛋白 预防和治疗老年人的T细胞免疫缺陷，从而改善医疗保健结果， 死亡率。