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: 10295388
• 负责人: Leyuan Ma
• 金额: $ 52.8万
• 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/10295388
• 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; Cytotoxic T-Lymphocytes; 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; Plant Roots; Postdoctoral Fellow; Reaction; Regulatory T-Lymphocyte; Route; Signal Transduction; Site; Source; Specificity; Synthetic Vaccines; T cell response; T-Lymphocyte; Tacrolimus; Technology; Tissues; Training; Translations; Transplantation; Transplantation Tolerance; Treg therapy; Vaccination; Vaccines; Vision; Work; allograft rejection; allotransplant; cancer therapy; cellular engineering; chimeric antigen receptor; chimeric antigen receptor T cells; curative treatments; cytotoxic; design; effective intervention; end-stage organ failure; graft vs host disease; immunological synapse; immunoregulation; improved; in vivo; lymph nodes; migration; preservation; prophylactic; receptor vaccine; response; technology development; 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患者的最终治疗选择 失败了。维持功能性同种异体移植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的寿命有限，因为慢性 由宿主同种异体免疫反应引发的排斥反应。大多数免疫抑制药 治疗的目标是效应器免疫细胞，如T细胞，离开根部 同种异体免疫反应-同种异体抗原呈递-原封不动并导致免疫 最终转向移植物排斥反应的平衡。调节性T细胞(Tregs)与用户- 可以利用特定的特异性在所需的组织中诱导免疫抑制。他们 也保持了通过接触依赖来耐受抗原提呈细胞(APC)的能力 蜂窝串扰。我们的愿景是开发一种强大的同种异体免疫调节策略 限制效应部位(同种异体移植)和同种异体抗原的同种免疫T细胞反应 呈现部位(移植物引流淋巴组织)将免疫平衡转移到长期 在完全保持宿主免疫系统剩余部分的同时抑制同种异体移植物 已投入使用。通过利用嵌合抗原受体(CAR)识别任何所需的 靶向和向淋巴特异性递送靶向的淋巴结靶向分子疫苗 节点APC，我们将设计一种正交合成疫苗来弥合CAR之间的串扰 Tregs和APC通过与其同源生物惰性配体的CAR定向相互作用合成 显示在APC上。这种合成疫苗介导的串扰将有两个结果：1)APC- TO-CAR Treg信号促进Car Treg扩张和向靶向同种异体移植物的迁移 具有增强的调节功能的抑制。2)CAR Treg-to-APC信令允许APC到 限制同种异体反应性T细胞启动促进诱导调节性T细胞的产生 (ITregs)，通过“感染耐受”实施自我维持的免疫抑制循环。我们 将在小鼠同种异体移植模型中评估合成串扰。如果成功，这将是 平台技术可以在广泛的环境中实施，以精确控制 病理情况，包括自身免疫性疾病、移植物抗宿主病和 移植排斥反应。