Antigen Loaded Particles for Tolerance Induction

描述(申请人提供)：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。史蒂芬·米勒(Stephen Miller)博士开创了一种方法，将脾细胞与特定的自身抗原交联，然后将其输送到脾中，诱导对自身抗原的特异性耐受。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。在这个提议中，我们开发了在静脉注射后以脾为靶点的颗粒，随后将被产生耐受性的抗原呈递细胞内化，在没有T细胞激活的情况下呈递抗原，从而诱导耐受性而不是免疫反应。大多数针对免疫系统的策略侧重于诱导特定的免疫反应(疫苗)，而这个系统的目标是通过诱导对特定抗原的耐受性来做相反的事情。我们假设，多肽连接的颗粒将被耐受性宿主辉煌的APC内化，这些APC随后通过协调诱导T细胞能量和激活限制T细胞反应的调节性T细胞来诱导免疫耐受。我们选择了具有生物相容性和生物降解性的材料，这些材料的物理性质可以控制以影响它们的分布，并可以用官能团进行修饰以促进内化，靶向特定的APC群体或受体，并可以释放生物活性蛋白来增强耐受反应。将研究以下目标：特异性目标1将研究免疫耐受诱导中脾归巢和抗原提呈的颗粒设计。具体目标2将研究与导致耐受的抗原相关颗粒相互作用的固有细胞机制。具体目标3将研究粒子引发的T细胞功能失活的机制，包括克隆缺失、能量/免疫偏离和Treg激活。这些研究的成功完成将确定新的、安全、有效和临床相关的颗粒，以抑制自身免疫性疾病治疗中的抗原特异性T细胞。这种创新的方法对于降低特定免疫反应可能是有益的应用具有深远的影响，例如自身免疫性疾病、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。 公共卫生相关性：在自身免疫性疾病中，如多发性硬化症，免疫系统攻击健康细胞，导致组织功能丧失，并使恢复能够提供这一功能的细胞的策略复杂化。我们建议开发可生物降解的、生物相容的颗粒，这种颗粒可以诱导耐受，从而特异性地防止免疫系统细胞的攻击。这一创新方法对降低特定免疫反应可能是有益的应用具有深远的影响，例如自身免疫性疾病、再生医学中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。

DESCRIPTION (provided by applicant): 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 crosslinked with specific autoantigens, and their delivery to the spleen induced tolerance specifically to the autoantigen. 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. In this proposal, we develop particles that target the spleen following intravenous delivery, and would subsequently be internalized by 'tolerogenic' antigen presenting cells to present the antigens without T cell activation thereby inducing tolerance rather than an immune response. Most strategies targeting the immune system focus on inducing a specific immune response (vaccines), whereas this system aims to do the opposite by inducing tolerance to specific antigens. We hypothesize that peptide-linked particles will be internalized by tolerogenic host splendid APCs which subsequently induce immune tolerance through the coordinate induction of T cell energy and activation of regulatory T cells that limit T cell responses. We have selected biocompatible and biodegradable materials whose physical properties can be controlled to influence their distribution, and can be modified with functional groups to promote internalization, target specific APC populations or receptors, and can release bioactive proteins to enhance the tolerogenic response. The following aims will be investigated: Specific Aim 1 will investigate particle design for splenic homing and antigen presentation in tolerance induction. Specific Aim 2 will investigate the innate cellular mechanisms that mediate interactions with antigen-linked particles that lead to tolerance. Specific Aim 3 will investigate mechanisms of particle-initiated inactivation of effectors T cell functions mediating tolerance induction including clonal deletion, energy/immune deviation, and Treg activation. 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 applications in which decreasing specific immune responses could be beneficial, such as the autoimmune diseases, rejection of transplanted cells, and allergies to food antigens or airborne particulates. PUBLIC HEALTH RELEVANCE: In autoimmune diseases, such as multiple sclerosis, the immune system attacks healthy cells resulting in the loss of tissue function, and also complicates strategies to restore cells that could provide that function. We propose to develop biodegradable, biocompatible particles that can induce tolerance and thereby specifically prevent the attack by cells of the immune system. This innovative approach has far reaching implications for applications in which decreasing specific immune responses could be beneficial, such as the autoimmune diseases, rejection of transplanted cells in regenerative medicine, and allergies to food antigens or airborne particulates.