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

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 通常伴随着慢性疾病，我们的免疫系统经常在 慢性疾病的发展和T细胞在免疫系统中起着关键作用，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，经历了 严重的年龄依赖性萎缩，这一过程称为胸腺退化。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，并难以建立 通过接种疫苗获得保护性免疫。目前，还没有有效的方法来预防或逆转T细胞 老年人中的免疫缺陷。胸腺中T细胞的发育依赖于胸腺 微环境，其中胸腺上皮细胞(TECs)是主要成分。然而，TEC经历了 质和量的丢失是导致胸腺萎缩的主要因素。 FOXN1是TEC开发和维护的关键调节器，我们已经证明 含有FOXN1和蛋白转导结构域(PTD)的重组(R)FOXN1融合蛋白可以 从细胞表面转移到细胞质和细胞核。胸腺内(I.T.)注射rFOXN1 融合蛋白进入小鼠体内可以增加TECs的数量，从而增强胸腺的生成和 增加外周T细胞的数量。然而，IT。注射途径对人类来说是不可行的 申请。就给药途径而言，有必要制定一种更可行的方案。 这项提议的目标是开发新的rFOXN1融合蛋白，这种融合蛋白可以迁移到胸腺中，从而 静脉注射、肌肉注射或皮下注射后增强胸腺生成。老年注射用药 老鼠。在R21期，我们将产生含有FOXN1-PTD和胸腺靶向的rFOXN1融合蛋白 多肽，或胸腺/TEC特异性受体或抗体(目标1)。然后我们将确定 RFOXN1融合蛋白在静脉注射、肌肉注射时迁移到胸腺。或者南加州大学。(目标2)，并增加 老年小鼠TECs和T细胞的数量(目标3)。如果达到了R21里程碑，R33阶段将是 承担了。目标4将进一步表征胸腺和外周T细胞在rFOXN1融合中的功能 蛋白质处理的老年小鼠。在目标5中，我们将确定rFOXN1融合蛋白处理的老年小鼠的T细胞 对自身抗原免疫耐受，以防止自身免疫。AIM 6将分析啮齿动物毒理学和 先导rFOXN1融合蛋白的药代动力学。我们的长期目标是使用领先的rFOXN1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和 死亡率。

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.