Graft Tolerance with Apoptotic Cells and Dendritic Cells

凋亡细胞和树突状细胞的移植物耐受性

• 批准号: 7388205
• 负责人: Adrian E. Morelli
• 金额: $ 34.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388205
• 关键词: Abdomen; Address; Adverse effects; Allogenic; Allografting; Antigens; Apoptosis; Apoptotic; Autoimmune Diseases; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Cells; Condition; Data; Dendritic Cells; Dose; Environment; Frequencies; Funding; Generations; Graft Rejection; Graft Tolerance; Grant; Immune Tolerance; Immune response; Immunity; Immunosuppression; Inflammatory; Kinetics; Knowledge; Laboratories; Leukocytes; Lymphoid; Maintenance; Modeling; Monitor; Mus; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Peptides; Peripheral; Phagocytosis; Pharmacological Treatment; Process; Property; Role; Signal Transduction; Staging; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Therapeutic immunosuppression; Tissues; Transference; Transplantation; anergy; autoreactive T cell; base; cytokine; heart allograft; in vivo; innovation

DESCRIPTION (provided by applicant): The main cause of transplant rejection is the immune response against donor allogeneic (allo) antigens (Ags) elicited by the recipient. Following transplant surgery, Dendritic cells (DCs) are the Ag-presenting cells that, as passenger leukocytes, present donor alloAgs to recipient T cells and trigger graft rejection. However, DCs also participate in induction of T cell tolerance. This tolerogenic property of DCs may be exploited to induce donor-specific T cell tolerance for treatment of allograft rejection or autoimmune diseases. There is evidence that phagocytosis of cells in early stages of apoptosis delivers a potent inhibitory signal to DCs. DCs that have internalized apoptotic cells downregulate expression of MHC and costimulatory molecules, decrease their T cell stimulatory capacity and reduce the synthesis of pro-inflammatory cytokines while maintaining high levels of TGF-B1. We propose to use the same principle to induce donor-specific tolerance to prolong cardiac allograft survival. This proposal will study the mechanism(s) by which early apoptotic cells exerts immuno-suppressive effects on DCs. It will test the hypothesis that administration of donor (MHC+) cells in early stages of apoptosis prolongs cardiac allograft survival by inducing anergy/apoptosis of alloreactive T cells or generation of allospecific T cells with regulatory function (Treg cells). We hypothesize that donor-specific T cell tolerance will be achieved by the following mechanisms: i) processing of donor apoptotic cells by recipient immature/semi-mature) DCs in the tolerogenic environment of secondary lymphoid organs (indirect pathway), ii) direct interaction of donor apoptotic/dying cells with recipient T cells (direct pathway); iii) transference of donor "intact" MHC molecules from donor apoptotic/dying cells to recipient DCs and iv) reduced synthesis of alloAbs, due to lack of allospecific CD4+ T cell help. This proposal will define the optimal conditions for the use of donor apoptotic cells to achieve long-term cardiac allograft survival as follows: i) by optimizing the dose, kinetics, frequency and efficiency of delivery of donor apoptotic cells; ii) by simultaneous targeting of the direct and indirect pathways and iii) by combination of donor apoptotic cells with suboptimal levels of immunosuppression. We propose to employ this approach to induce donor-specific tolerance in heart allograft recipients as an alternative to pharmacological treatments that induce generalized immunosuppression and harmful side effects. The knowledge gained will clarify the therapeutic potential of administration of donor cells in early stages of apoptosis to target recipient DCs in vivo to promote donor-specific tolerance. We will address the following specific aims: Aim 1; To study the effect that early apoptotic cells exerts on the allostimulatory function of DCs. Aim 2: To monitor in vivo the effect of allogeneic apoptotic cells on allospecific T and B cell immune responses. Aim 3; To optimize the therapeutic effect of donor apoptotic cells on heart allograft survival. To investigate the mechanism(s) of action of donor apoptotic cells in graft recipients.

描述（由申请人提供）：移植排斥的主要原因是受者引起的针对供体同种异体（allo）抗原（Ag）的免疫反应。移植手术后，树突状细胞 (DC) 是抗原呈递细胞，作为过客白细胞，将供体同种抗原呈递给受体 T 细胞并引发移植物排斥。然而，DC 也参与 T 细胞耐受的诱导。 DC 的这种致耐受特性可用于诱导供体特异性 T 细胞耐受，从而治疗同种异体移植排斥或自身免疫性疾病。有证据表明细胞凋亡早期阶段的细胞吞噬作用向 DC 传递有效的抑制信号。内化凋亡细胞的 DC 会下调 MHC 和共刺激分子的表达，降低其 T 细胞刺激能力并减少促炎细胞因子的合成，同时维持高水平的 TGF-B1。我们建议使用相同的原理来诱导供体特异性耐受，以延长同种异体心脏移植物的存活率。该提案将研究早期凋亡细胞对树突状细胞发挥免疫抑制作用的机制。它将检验这样的假设：在细胞凋亡的早期阶段给予供体 (MHC+) 细胞，可以通过诱导同种异体反应性 T 细胞的无反应性/细胞凋亡或产生具有调节功能的同种异体特异性 T 细胞（Treg 细胞）来延长心脏同种异体移植物的存活。我们假设供体特异性 T 细胞耐受将通过以下机制实现：i) 受者未成熟/半成熟的 DC 在次级淋巴器官的耐受环境中处理供体凋亡细胞（间接途径），ii) 直接相互作用供体凋亡/垂死细胞与受体 T 细胞（直接途径）； iii) 供体“完整”MHC 分子从供体凋亡/垂死细胞转移至受体 DC，以及 iv) 由于缺乏同种异体特异性 CD4+ T 细胞的帮助，同种抗体的合成减少。该提案将定义使用供体凋亡细胞实现长期心脏同种异体移植物存活的最佳条件，具体如下：i) 通过优化供体凋亡细胞的递送剂量、动力学、频率和效率； ii) 通过同时靶向直接和间接途径，以及 iii) 通过将供体凋亡细胞与次优水平的免疫抑制相结合。我们建议采用这种方法来诱导心脏同种异体移植受者的供体特异性耐受，作为诱导全身免疫抑制和有害副作用的药物治疗的替代方案。所获得的知识将阐明在细胞凋亡早期阶段给予供体细胞以体内靶向受体树突状细胞以促进供体特异性耐受的治疗潜力。我们将实现以下具体目标：目标 1；研究早期凋亡细胞对DC同种刺激功能的影响。目标 2：体内监测同种异体凋亡细胞对同种异体特异性 T 和 B 细胞免疫反应的影响。目标3；优化供体凋亡细胞对心脏同种异体移植物存活的治疗效果。研究供体凋亡细胞在移植受者中的作用机制。

项目成果

Dendritic cell therapies in transplantation revisited: deletion of recipient DCs deters the effect of therapeutic DCs.

• DOI: 10.1111/j.1600-6143.2012.04060.x
• 发表时间: 2012-06
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Wang Z;Divito SJ;Shufesky WJ;Sumpter T;Wang H;Tkacheva OA;Wang W;Liu C;Larregina AT;Morelli AE
• 通讯作者: Morelli AE