Dendritic Cell Ligation of Complement Receptor 3 in Transplanation Tolerance

补体受体 3 树突状细胞连接对移植耐受的影响

• 批准号: 7589459
• 负责人: STEFANIA GALLUCCI
• 金额: $ 6.79万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2009-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589459
• 关键词: Affect; Agonist; Animals; Apoptotic; Autoimmunity; Binding; Biological Factors; Biological Response Modifier Therapy; C3bi; CD8B1 gene; Cell physiology; Cells; Clinical; Complement; Data; Dendritic Cells; Dendritic cell activation; Experimental Models; Exploratory/Developmental Grant; Failure; Goals; Graft Rejection; Immune; Immune response; Immune system; Immunization; Immunoglobulin Class Switching; Immunosuppressive Agents; Immunotherapy; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Infusion procedures; Injection of therapeutic agent; Interleukin-12; Interleukin-6; Lead; Ligation; Link; Macrophage-1 Antigen; Mediating; Minor Histocompatibility Antigens; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myelogenous; Operative Surgical Procedures; Organ Transplantation; Patients; Population Heterogeneity; Procedures; Production; Protocols documentation; Psoriasis; Radiation; Role; S cerevisiae SWI3 protein; Skin; Skin Transplantation; Skin graft; Solid; Stem cell transplant; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissue Transplantation; Tissues; Transforming Growth Factor beta; Transplantation; Transplantation Tolerance; Work; anergy; chemotherapy; conditioning; cytokine; immunogenic; improved; in vivo; mortality; novel; prevent; public health relevance; receptor; research study; response; success

DESCRIPTION (provided by applicant): A successful transplantation requires the acceptance of the graft by the immune system. The activation of Dendritic cells (DCs) occurring during the transplantation procedure is an important cause of immunization against the graft and therefore of its rejection. A suppression of DC activation that could divert them from stimulating the immune response against the graft, it would allow induction of T cell tolerance and strongly improve the chances of success of any graft. We have recently discovered that the ligation of the Complement Receptor 3 (CR3), which is present on myeloid DCs and is normally bound by opsonized apoptotic cells, with a monoclonal Ab suppresses the ability of murine DCs to express pro-inflammatory cytokines such as IL-12 and TNFa and stimulate CD4 and CD8 T cells. Furthermore, CR3 ligation of DCs can bias their expression of cytokines toward a tolerogenic profile dominated by TGF-beta production and leading to T cell tolerance. In this exploratory project, we propose to determine the effects of the agonistic ligation of CR3 in preventing and suppressing graft rejection in experimental models of solid organ transplantation and begin to understand the underlying mechanisms. In particular, we propose in Aim 1 to determine the effects of CR3-ligation on the rejection of skin grafts. We will investigate the effects of the infusion of agonist anti-CR3 Abs in the acceptance of skin grafts through a single minor histocompatibility antigen (HY) barrier in a spontaneous model and in one induced by TLR stimulation. In Aim 2, we will determine how CR3 ligation affects DC functions and the subsequent T cell responses against the skin grafts and through which cellular mechanisms. We will explore four possible T cells responses that have been implicated in the induction of tolerance in other systems graft tolerization: 1) inhibition of effector T cell response; 2) class switch; 3) deletion and anergy; and 4) T regulatory cell induction. This application aims to determine whether and how anti-CR3 therapy can be a new Ab therapy in the induction of tolerance in transplantation. Our fundamental goal is to generate a therapeutic protocol that can quickly and directly be applied first to larger animals and eventually to transplantation patients, in combination with the present immunosuppressive regime and, ultimately, in a novel tolerogenic regime. PUBLIC HEALTH RELEVANCE: We have recently discovered that the ligation of Complement Receptor 3 by a monoclonal antibody suppresses the immunogenic functions of dendritic cells. This exploratory project will test the role of this novel immunosuppressive agent in preventing and suppressing graft rejection in experimental models of solid organ transplantation. Our long-term goal is to discover biologic factors able to induce a stable tolerogenic function in dendritic cells that can be used in immunotherapy of conditions, such as transplantation and autoimmunity, in which excessive and inappropriate immune responses are causing morbidity and mortality.

描述（由申请人提供）：成功的移植需要免疫系统接受移植物。在移植过程中发生的树突状细胞（DC）的活化是针对移植物的免疫并因此其排斥的重要原因。抑制DC活化可以使它们从刺激针对移植物的免疫反应中转移出来，这将允许诱导T细胞耐受并大大提高任何移植物的成功机会。我们最近发现，补体受体3（CR 3）与单克隆抗体的连接抑制了鼠DC表达促炎细胞因子（如IL-12和TNF α）并刺激CD 4和CD 8 T细胞的能力，所述补体受体3存在于髓样DC上并通常被调理的凋亡细胞结合。此外，DC的CR 3连接可以使它们的细胞因子表达偏向由TGF-β产生主导的致耐受性谱，并导致T细胞耐受。在这个探索性的项目中，我们建议确定激动性连接CR 3在实体器官移植实验模型中预防和抑制移植物排斥反应的效果，并开始了解潜在的机制。特别是，我们在目标1中提出确定CR 3-结扎对皮肤移植物排斥反应的影响。我们将在自发模型和TLR刺激诱导模型中研究激动剂抗CR 3抗体输注通过单个次要组织相容性抗原（HY）屏障对皮肤移植物接受的影响。在目标2中，我们将确定CR 3连接如何影响DC功能和随后的T细胞对皮肤移植物的反应，以及通过哪些细胞机制。我们将探索在其他系统移植物耐受化中诱导耐受所涉及的四种可能的T细胞应答：1）抑制效应T细胞应答; 2）类别转换; 3）缺失和无反应性;和4）调节性T细胞诱导。本申请旨在确定抗CR 3治疗是否以及如何成为诱导移植耐受的新Ab治疗。我们的基本目标是产生一种治疗方案，该方案可以快速和直接地首先应用于较大的动物，并最终应用于移植患者，与目前的免疫抑制方案相结合，并最终应用于新的致耐受性方案。 公共卫生关系：我们最近发现，补体受体3的单克隆抗体的连接抑制树突状细胞的免疫原性功能。这个探索性项目将在实体器官移植实验模型中测试这种新型免疫抑制剂在预防和抑制移植物排斥反应中的作用。我们的长期目标是发现能够在树突状细胞中诱导稳定的致耐受性功能的生物因子，所述树突状细胞可用于疾病的免疫治疗，例如移植和自身免疫，其中过度和不适当的免疫应答导致发病和死亡。