Dendritic Cell Ligation of Complement Receptor 3 in Transplanation Tolerance

描述(申请人提供)：成功的移植需要免疫系统接受移植物。树突状细胞(DC)在移植过程中的激活是移植物免疫和排斥反应的重要原因。抑制DC的激活可以转移他们刺激对移植物的免疫反应，这将允许诱导T细胞耐受，并极大地提高任何移植物的成功机会。我们最近发现，补体受体3(CR3)存在于髓系树突状细胞上，通常与调理的凋亡细胞结合，与单抗结合会抑制小鼠树突状细胞表达促炎细胞因子如IL-12和TNFa的能力，并刺激CD4和CD8T细胞。此外，CR3结扎DC可以使其细胞因子的表达偏向于以转化生长因子-β的产生为主的耐受性特征，从而导致T细胞耐受。在这个探索性的项目中，我们建议在实体器官移植的实验模型中确定激活性结扎CR3在预防和抑制移植物排斥反应中的作用，并开始了解其潜在的机制。特别是，我们在目标1中建议确定CR3-结扎对皮肤移植物排斥反应的影响。在自发皮肤移植模型和TLR刺激皮肤移植模型中，我们将研究注射激动剂抗CR3抗体对皮肤移植物通过单一次要组织相容抗原(HY)屏障接受的影响。在目标2中，我们将确定CR3结扎如何影响DC功能和随后对皮肤移植物的T细胞反应，以及通过哪些细胞机制。我们将探讨在其他系统的移植物耐受中诱导耐受的四种可能的T细胞反应：1)抑制效应T细胞反应；2)类别转换；3)缺失和无能；以及4)T调节细胞的诱导。这项应用旨在确定抗CR3疗法是否以及如何成为诱导移植耐受的一种新的抗体疗法。我们的基本目标是产生一种治疗方案，该方案可以快速而直接地首先应用于较大的动物，最终应用于移植患者，与目前的免疫抑制方案相结合，最终应用于一种新的耐受方案。 公共卫生相关性：我们最近发现，补体受体3被单抗连接会抑制树突状细胞的免疫原性功能。这一探索性项目将在固体器官移植的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耐受功能的生物因素，这些因素可以用于移植和自身免疫等疾病的免疫治疗，在这些条件下，过度和不适当的免疫反应会导致发病率和死亡率。

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.