Engineering synthetic cellular crosstalk for transplantation tolerance

工程合成细胞串扰以实现移植耐受

基本信息

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
项目类别：
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

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

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项目摘要

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.

器官移植仍然是终阶段器官患者的确定治疗选择失败。功能同种异体移植的维持要求器官受体保持免疫 - 抑制药物。但是，由于慢性主机同种免疫反应引发的拒绝。大多数免疫抑制治疗针对效应免疫细胞，例如T细胞，留下 Allomune的反应（Alloantigen表现）不受欢迎并导致免疫最终转向移植排斥的平衡。具有用户的调节性T细胞（Tregs）可以利用定义的特异性在所需组织中诱导免疫抑制。他们还可以保持通过接触依赖性耐受抗原呈递细胞（APC）的能力细胞串扰。我们的愿景是制定强大的同种特定免疫调节策略限制在效应部位（同种异体移植）和同种抗原的同种免疫T细胞响应演示位点（移植物绘制淋巴组织）以将相当于长期的免疫在同种异体移植中抑制，同时保持剩余的宿主免疫系统的全部抑制操作。通过利用嵌合抗原受体（CAR）识别任何所需的能力靶向分子疫苗的靶标和淋巴结，以特异性赋予靶向淋巴节点APC，我们将设计一种正交合成疫苗，以桥接汽车之间的串扰 Tregs和APC通过CAR定向的相互作用与其同源生物iNert配体合成显示在APC上。该合成疫苗介导的串扰将有两个结果：1）APC- TO-CAR Treg信令促进了Car Treg的扩展，并迁移到同种异体移植通过增强的调节功能抑制。 2）CAR TREG-TO-APC信号传导可容忍APC 限制同种异体T细胞启动并促进诱导的调节T细胞的产生（ITREGS），它通过“传染性耐受性”来实施自我维持的免疫抑制循环。我们将评估鼠同种异体移植模型中的合成串扰。如果成功，这平台技术可以在广阔的景观中实施，以精确控制病理状况，包括自身免疫性疾病，移植物抗宿主病和移植排斥。