Peptide-dependent mobilization of CD8 regulatory cells in cardiac transplantation

心脏移植中 CD8 调节细胞的肽依赖性动员

• 批准号: 10585628
• 负责人: Jamil Azzi
• 金额: $ 68.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585628
• 关键词: Address; Agonist; Alloantigen; Allografting; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; C-Type Lectins; CD4 Positive T Lymphocytes; CD8 receptor; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chronic; Clinical Data; Complex; Data; Engineering; Generations; Genes; Genetic; Genetic Polymorphism; Graft Rejection; Graft Survival; Heart; Heart Transplantation; Helper-Inducer T-Lymphocyte; Homologous Transplantation; Human; Immune response; Infection; Injury; Isoantibodies; Kidney; Kidney Transplantation; Knockout Mice; Libraries; Lymphocytic choriomeningitis virus; Major Histocompatibility Complex; Mediating; Membrane Glycoproteins; Modeling; Mus; Mutagenesis; Mutation; NK cell receptor NKB1; Natural Killer Cells; Organ Transplantation; Outcome; Pathogenicity; Peptide Hydrolases; Peptide Library; Peptides; Positioning Attribute; Production; Proteins; Publishing; Qa-1 Antigen; Reaction; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Solid; Specificity; Stress; Study models; Surface; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissue Grafts; Tissues; Variant; Yeasts; clinical application; cohort; combinatorial; donor-specific antibody; heart allograft; improved; insight; isoimmunity; mouse model; novel; novel strategies; pathogen; receptor; receptor expression; response; selective expression; synthetic peptide; transplant model; treatment strategy; vaccine strategy

Project Summary Antibody-mediated graft rejection (AMR) remains a major barrier to successful solid organ transplantation. Establishing novel treatment strategies based on our understanding of underlying mechanisms may improve long term graft outcomes. Although pathogenic allo-antibodies mediating AMR are produced mainly by GC B cells after induction by follicular T helper (Tfh) cells, regulation of this response is poorly understood. Insight into mechanisms that regulate these GC responses and dampen AMR to improve heart allograft outcomes are needed. We have uncovered and exploited a central role for Qa-1-/HLA-E-restricted CD8 regulatory T cells in the control of Tfh-dependent DSA responses against donor allografts. Our published and preliminary experimental data indicate that CD8 Treg that are restricted by class Ib MHC (murine Qa-1/human HLA-E) can be mobilized by synthetic FL9 peptides to inhibit alloimmune Tfh cells, dampen Ab-mediated injury and prolong heart allograft survival in fully mismatched heart transplant models. These findings open the possibility of HLA-E-targeted vaccine strategies that exploit the limited polymorphism of this MHC class Ib gene and avoid problems of class Ia MHC diversity. The FL9−Qa-1 complex is upregulated by a subset of activated Tfh cells that drive alloantibody responses. Identification of synthetic FL9 agonist peptides that mobilize Ag-specific CD8 Treg after a screen of a yeast peptide library based on the FL9 self-peptide is outlined in SA1. Analysis of mechanisms that underpin peptide- induced regulation of AMR against heart allografts are addressed in SA2. Targeting of co-receptors that modulate CD8 Treg activation and function are the subject of SA3. These studies should allow new and effective approaches to reduce AMR and improve allograft survival.

项目摘要 抗体介导的移植排斥反应（AMR）仍然是实体器官移植成功的主要障碍。 根据我们对潜在机制的理解建立新的治疗策略可能会改善 长期移植结果。虽然介导AMR的致病性同种抗体主要由GC B产生 滤泡性T辅助细胞（Tfh）诱导后，这种反应的调节知之甚少。洞察 调节这些GC反应和抑制AMR以改善心脏移植物结局的机制是 needed. 我们已经发现并利用了Qa-1-/HLA-E-限制性CD 8调节性T细胞在对照组中的核心作用。 对供体同种异体移植物的Tfh依赖性DSA反应。我们发表的和初步的实验数据 表明受Ib类MHC（鼠Qa-1/人HLA-E）限制CD 8 Treg可通过 合成FL 9肽抑制同种免疫Tfh细胞，抑制Ab介导的损伤并延长心脏同种异体移植 在完全不匹配的心脏移植模型中的存活率。这些发现开启了HLA-E靶向治疗的可能性。 利用这种MHC Ib类基因的有限多态性并避免MHC Ib类问题的疫苗策略， Ia MHC多样性。 FL 9 −Qa-1复合物被激活的Tfh细胞亚群上调，这些细胞驱动同种抗体反应。 在酵母筛选后鉴定动员Ag特异性CD 8 Treg的合成FL 9激动剂肽 基于FL 9自身肽的肽文库概述于SA 1中。分析支持肽- 针对心脏同种异体移植物的AMR的诱导调节在SA 2中论述。靶向共受体， 调节CD 8 Treg的活化和功能是SA 3的主题。这些研究应该允许新的和有效的 减少AMR和提高同种异体移植物存活率的方法。