Antigen loaded particles for tolerance induction

 描述：免疫系统对健康细胞的不受欢迎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。目前对自身免疫性疾病的标准治疗包括全身性免疫抑制，在大多数情况下，这在临床上是无效的，并导致许多不受欢迎的副作用。斯蒂芬·米勒博士(合作者)开创了一种方法，将脾细胞与特定的自身抗原交联，然后将其输送到脾中，诱导对自身的特异性耐受 抗原。这种方法最近被用于多发性硬化症(MS)患者的临床试验，并且是第一个报道诱导抗原特异性耐受的人的研究。然而，使用细胞载体在临床上诱导耐受是具有挑战性的，因为需要相当多的体外实验室操作，这是昂贵的，增加了所需的供体细胞的数量，并带来了进一步的技术错误的机会。我们的长期目标是开发一种基于颗粒的平台，它可以是一种现成的产品，用于诱导对特定抗原的耐受，以抑制特定的不受欢迎的免疫反应，同时不改变免疫反应的剩余成分。我们已经证明，通过静脉注射携带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)的耐受性，这是MS的小鼠模型。为了将这项技术推向临床，我们建议扩展这些研究，以解决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疾病潜在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，肝脏是参与从颗粒中诱导耐受的关键部位，这将其区分开来 来自之前对抗原偶联的脾细胞的研究。我们建议研究颗粒的组成和大小，以区分i)载体对免疫细胞极化的影响，ii)抗原提呈的有效性，以及iii)颗粒的体内运输。具体目的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。我们建议用包裹多个多肽/蛋白质的颗粒来测试诱导耐受的能力，并检查无能和Tregs在诱导和维持耐受中的单独和联合作用。成功完成这些研究将确定新的、安全的、高效的和 抑制抗原特异性T细胞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自身免疫性疾病、移植细胞的排斥反应以及对食物抗原或空气颗粒物的过敏等应用中的特定免疫反应具有深远的影响。

 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.