Antigen loaded particles for tolerance induction

 产品说明：免疫系统对健康细胞的不希望的破坏导致组织功能的丧失，并使恢复组织功能的策略复杂化。目前用于自身免疫性疾病的标准疗法涉及全身性免疫抑制，其在大多数情况下在临床上是无效的并且导致许多不期望的副作用。Stephen米勒博士（共同PI）开创了一种方法，其中脾细胞与特异性自身抗原交联，并将其递送至脾诱导特异性对自身抗原的耐受性。 抗原的这种方法最近被用于多发性硬化症（MS）患者的临床试验，并且是第一个报告诱导抗原特异性耐受的人体研究。然而，在临床竞技场中使用细胞载体诱导耐受性是具有挑战性的，因为需要相当多的离体实验室操作，这是昂贵的，增加了所需的供体细胞的数量，并引入了技术错误的进一步机会。我们的长期目标是开发一种基于颗粒的平台，该平台可以是现成的产品，用于诱导对特定抗原的耐受性，以抑制特定的非预期免疫应答，同时不改变免疫应答的其余元素。我们已经证明，静脉内递送的负载抗原的颗粒可以诱导预防和治疗实验性自身免疫性脑脊髓炎（EAE）（MS的小鼠模型）的耐受性。为了将这种技术推向临床，我们建议扩展这些研究以解决有关颗粒设计及其作用机制的基本问题，以及关于靶向各种抗原和潜在疾病的细胞群的能力的关键问题。具体目标1将研究颗粒设计参数，并确定静脉注射颗粒能够调节炎症和诱导抗原特异性耐受的细胞机制。我们的结果表明，肝脏是参与颗粒耐受诱导的关键部位，这使其与众不同 从先前的抗原偶联的脾细胞的工作。我们建议研究颗粒组成和尺寸以区分i）载体对免疫细胞极化的影响，ii）抗原呈递的功效，和iii）颗粒的体内运输。特异性目的2将确定在幼稚、活化和记忆T细胞中诱导和维持Ag-PLG耐受的细胞和分子机制。我们建议测试的能力，以诱导耐受性的颗粒封装多个肽/蛋白质和检查的单独和合并的贡献的无反应性和Tclase的诱导和维持的耐受性。这些研究的成功完成将确定新的，安全的，有效的， 抑制抗原特异性T细胞以治疗自身免疫性疾病的临床相关工具。这种创新的方法对于减少应用中的特异性免疫反应具有深远的意义，例如自身免疫性疾病，移植细胞的排斥，以及对食物抗原或空气中颗粒物的过敏。

 DESCRIPTION: The undesired destruction of healthy cells by the immune system results in the loss of tissue function and complicates strategies to restore tissue function. The current standard therapy for autoimmune disease involves generalized immunosuppression, which is in most cases is not clinically efficacious and leads to numerous undesired side effects. Dr. Stephen Miller, (co-PI) pioneered an approach in which splenocytes were cross-linked with specific auto antigens, and their delivery to the spleen induced tolerance specifically to the auto antigen. This approach was recently adapted for a clinical trial in multiple sclerosis (MS) patients, and was the first-in-man study to report the induction antigen specific tolerance. However, the use of cellular carriers for tolerance induction in the clinical arena is challenging due to the considerable ex-vivo laboratory manipulation that is required, which is expensive, increases the number of donor cells needed and introduces further opportunity for technical error. Our long-term goal is to develop a particle-based platform that can be an off-the-shelf product for induction of tolerance to specific antigens to inhibit the specific undesired immune response while not altering the remaining elements of the immune response. We have demonstrated that antigen-loaded particles delivered intravenously can induce tolerance for the prevention and treatment of experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. With the goal of moving this technology toward the clinic, we propose to extend these studies to address fundamental questions about the particle design and their mechanisms of action, and also critical questions regarding the ability to target the variety of antigens and cell populations underlying disease. Specific Aim 1 will investigate the particle design parameters and identify the cellular mechanisms by which particles injected intravenously are able to modulate inflammation and induce antigen specific tolerance. Our results suggest the liver as a critical site involved in tolerance induction from the particles, which distinguishes it from the previous work with antigen-coupled splenocytes. We propose to investigate the particle composition and size to distinguish i) the impact of the carrier on immune cell polarization, ii) te efficacy of antigen presentation, and iii) in vivo trafficking of the particles. Specific Aim 2 wil determine the cellular and molecular mechanisms by which Ag-PLG tolerance is induced and maintained in naïve, activated, and memory T cells. We propose to test the ability to induce tolerance with particles encapsulating multiple peptides/proteins and to examine the separate and combined contributions of anergy and Tregs to the induction and maintenance of tolerance. Successful completion of these studies would identify particles that are novel, safe, efficient and clinically relevant tools to inhibit antigen-specific T-cells for therapy of autoimmune diseases. This innovative approach has far reaching implications for decreasing specific immune responses in applications such as autoimmune disease, rejection of transplanted cells, and allergies to food antigens or airborne particulates.