Antigen Loaded Particles for Tolerance Induction

描述（由申请人提供）：免疫系统对健康细胞的非预期破坏导致组织功能丧失，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。在临床竞技场中使用细胞载体进行耐受性诱导是具有挑战性的，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。在该提议中，我们开发了在静脉内递送后靶向脾的颗粒，并且随后将被“致耐受性”抗原呈递细胞内化以呈递抗原而没有T细胞活化，从而诱导耐受性而不是免疫应答。针对免疫系统的大多数策略集中于诱导特异性免疫应答（疫苗），而该系统旨在通过诱导对特异性抗原的耐受来实现相反的目的。我们假设肽连接的颗粒将被致耐受性宿主出色的APC内化，随后通过协调诱导T细胞能量和激活限制T细胞应答的调节性T细胞来诱导免疫耐受。我们选择了生物相容性和生物可降解的材料，其物理性质可以控制以影响其分布，并且可以用官能团修饰以促进内化，靶向特定的APC群体或受体，并且可以释放生物活性蛋白以增强致耐受性反应。将研究以下目标：具体目标1将研究耐受诱导中脾脏归巢和抗原提呈的颗粒设计。具体目标2将研究介导与导致耐受性的抗原连接颗粒相互作用的先天细胞机制。具体目标3将研究介导耐受诱导的效应T细胞功能的颗粒启动失活机制，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鉴定作为抑制抗原特异性T细胞用于治疗自身免疫性疾病的新型、安全、有效和临床相关工具的颗粒。这种创新的方法对于减少特异性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，以及对食物抗原或空气中颗粒物的过敏。 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，并且还使恢复可以提供该功能的细胞的策略复杂化。我们建议开发可生物降解的，生物相容性的颗粒，可以诱导耐受性，从而特异性地防止免疫系统细胞的攻击。这种创新的方法对减少特定免疫反应可能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中颗粒物的过敏。

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.