Dendritic Cell Ligation of Complement Receptor 3 in Transplanation Tolerance

描述（由申请人提供）：成功的移植需要移植物被免疫系统接受。在移植过程中发生的树突状细胞（dc）的活化是对移植物免疫的重要原因，因此也导致了移植物的排斥反应。抑制DC激活可以转移它们对移植物的免疫反应，它可以诱导T细胞耐受，并大大提高任何移植物成功的机会。我们最近发现，补体受体3 （CR3）与单克隆抗体的结合抑制了小鼠dc表达IL-12和TNFa等促炎细胞因子和刺激CD4和CD8 T细胞的能力。补体受体3存在于髓系dc上，通常由活化的凋亡细胞结合。此外，dc的CR3连接可以使其细胞因子的表达偏向于由tgf - β产生主导的耐受性特征，并导致T细胞耐受性。在这个探索性项目中，我们建议在实体器官移植实验模型中确定CR3的拮抗结扎在预防和抑制移植排斥反应中的作用，并开始了解其潜在机制。特别是，我们在Aim 1中提出确定cr3结扎对皮肤移植排斥反应的影响。我们将在自发模型和TLR刺激诱导的模型中研究通过单一次要组织相容性抗原（HY）屏障输注激动剂抗cr3抗体对皮肤移植接受的影响。在Aim 2中，我们将确定CR3结扎如何影响DC功能和随后的T细胞对皮肤移植物的反应，以及通过哪种细胞机制。我们将探讨四种可能的T细胞反应，这些反应与其他系统中移植物耐受的诱导有关：1)抑制效应T细胞反应；2)类开关；3)删减与能量；4) T调节性细胞诱导。本应用旨在确定抗cr3治疗是否以及如何成为一种新的抗体治疗在移植中诱导耐受。我们的基本目标是产生一种治疗方案，可以快速直接地首先应用于大型动物，最终应用于移植患者，结合目前的免疫抑制方案，并最终应用于一种新的耐受性方案。

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.