Engineering synthetic cellular crosstalk for transplantation tolerance

工程合成细胞串扰以实现移植耐受

• 批准号: 10557904
• 负责人: Leyuan Ma
• 金额: $ 52.72万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557904
• 关键词: Acute; Adoptive Cell Transfers; Age; Alloantigen; Allografting; Antigen-Presenting Cells; Antigens; Antithymoglobulin; Autoimmune Diseases; Biological; Biology; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cross Presentation; Cytotoxic T-Lymphocytes; Disease; Dose; Engineering; Equilibrium; Generations; Genetic; Genetic Polymorphism; Goals; Graft Rejection; Homeostasis; Human; Immune; Immune system; Immunity; Immunologic Surveillance; Immunology; Immunosuppression; Immunosuppressive Agents; Investigation; Kinetics; Ligands; Longevity; Lymphoid Tissue; Maintenance; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Medical; Modeling; Molecular; Molecular Target; Molecular Vaccines; Mus; Nature; Opportunistic Infections; Organ; Organ Transplantation; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Phenotype; Postdoctoral Fellow; Reaction; Regulatory T-Lymphocyte; Route; Signal Transduction; Site; Source; Specificity; Synthetic Vaccines; T cell response; T cell therapy; T-Lymphocyte; Tacrolimus; Tissues; Training; Translations; Transplantation; Transplantation Tolerance; Vaccination; Vaccines; Vision; Work; allotransplant; amphiphilicity; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; curative treatments; cytotoxic; design; effective intervention; end-stage organ failure; graft vs host disease; immunological synapse; immunomodulatory strategy; immunoregulation; improved; in vivo; lymph nodes; migration; preservation; prophylactic; receptor vaccine; response; synergism; technology development; technology platform; therapeutic evaluation; vaccination strategy; vaccine development; vaccine response

Organ transplantation remains the definitive treatment option for patients with end-stage organ failure. Maintenance of functional allografts requires organ recipients to stay on immune- suppressive drugs. However, most allografts have a limited lifespan because of the chronic rejection initiated by the host alloimmune responses. The majority of immunosuppressive treatments are targeted to the effector immune cells, such as T cells, leaving the root of alloimmune responses—alloantigen presentation—untouched and leading to an immune equilibrium which eventually is shifted toward graft rejection. Regulatory T cells (Tregs) with user- defined specificity could be harnessed to induce immune suppression at desired tissues. They also preserve the ability to tolerize antigen-presenting cells (APCs) through contact-dependent cellular crosstalk. Our vision is to develop a robust allospecific immune regulatory strategy that restricts alloimmune T cell responses at both the effector site (allograft) and the alloantigen presentation site(graft draining lymphoid tissue) to shift the immune equilibrium to long-term suppression in the allograft while keeping the remainder of the host immune system fully operational. By leveraging the ability of chimeric antigen receptor (CAR) to recognize any desired target and a lymph node targeting molecular vaccine to specifically deliver the target to lymph node APCs, we will engineer an orthogonal synthetic vaccine to bridge crosstalk between CAR Tregs and APCs via the CAR-directed interaction with its cognate bio-inert ligand synthetically displayed on APCs. This synthetic vaccine-mediated crosstalk will have two outcomes: 1) APC- to-CAR Treg signaling promotes CAR Treg expansion and migration to the allograft for targeted suppression with enhanced regulatory functions. 2) CAR Treg-to-APC signaling tolerizes APC to restrict alloreactive T cell priming and to promote the generation of induced regulatory T cells (iTregs), which enforces a self-sustaining immunosuppression cycle via “infectious tolerance”. We will evaluate the synthetic crosstalk in murine allotransplantation models. If successful, this platform technology could be implemented across a broad landscape for precision control of pathological conditions, including autoimmune diseases, graft-versus-host disease, and transplant rejection.

器官移植仍然是终末期器官移植患者的最终治疗选择。 失败功能性同种异体移植物的维持需要器官接受者保持免疫- 抑制性药物然而，大多数同种异体移植物由于慢性炎症而具有有限的寿命。 由宿主同种免疫反应引发的排斥反应。大多数免疫抑制剂 治疗靶向效应免疫细胞，如T细胞，留下免疫缺陷的根源。 同种免疫反应-同种抗原呈递-未触及并导致免疫 平衡最终向移植排斥转移。调节性T细胞（Tcells）与用户- 可以利用确定的特异性在所需组织诱导免疫抑制。他们 也保留了通过接触依赖性免疫耐受抗原呈递细胞（APC）的能力， 蜂窝串话我们的愿景是开发一种强大的同种特异性免疫调节策略， 限制效应部位（同种异体移植物）和同种异体抗原处的同种免疫T细胞应答 呈递部位（移植物引流淋巴组织）将免疫平衡转移到长期 抑制同种异体移植物，同时保持宿主免疫系统的其余部分完全 操作。通过利用嵌合抗原受体（CAR）识别任何所需抗原的能力， 靶点和淋巴结靶向分子疫苗，以将靶点特异性递送至淋巴 节点APC，我们将设计一种正交合成疫苗来桥接CAR之间的串扰， 通过CAR指导的与其同源生物惰性配体的相互作用，合成TcR和APC 展示在APC上。这种合成疫苗介导的串扰将具有两个结果：1）APC- to-CAR Treg信号传导促进CAR Treg扩增和迁移至同种异体移植物，以靶向 具有增强的调节功能的抑制。2)CAR Treg至APC信号传导耐受APC 限制同种异体反应性T细胞引发并促进诱导调节性T细胞的产生 免疫抑制剂（iTHBE），其通过“感染耐受性”实施自我维持的免疫抑制循环。我们 将在鼠同种异体移植模型中评估合成串扰。如果成功，这 平台技术可以在广泛的环境中实施，以精确控制 病理状况，包括自身免疫性疾病、移植物抗宿主病，以及 移植排斥反应