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：
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
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/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

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.

器官移植仍然是终末期器官患者的最终治疗选择维持功能性同种异体移植物的失败需要器官接受者保持免疫状态。然而，由于慢性病，大多数同种异体移植物的寿命有限。排斥反应由宿主同种免疫反应引发。治疗针对效应免疫细胞，例如 T 细胞，从而从根本上解决问题同种免疫反应——同种抗原呈递——未受影响并导致免疫平衡最终转向移植物排斥。可以利用确定的特异性来诱导所需组织的免疫抑制。还通过接触依赖性保留了对抗原呈递细胞 (APC) 的耐受能力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位点（同种异体移植物）和同种抗原的同种免疫 T 细胞反应呈现部位（移植引流淋巴组织）将免疫平衡转变为长期抑制同种异体移植物，同时充分保留宿主免疫系统的其余部分通过利用嵌合抗原受体（CAR）的能力来识别任何所需的。靶点和淋巴结靶向分子疫苗，将靶点特异性递送至淋巴结节点 APC，我们将设计一种正交合成疫苗来桥接 CAR 之间的串扰 Tregs 和 APC 通过 CAR 引导与其同源生物惰性配体合成相互作用这种合成疫苗介导的串扰将产生两个结果：1) APC- to-CAR Treg 信号传导促进 CAR Treg 扩增并迁移至同种异体移植物，以实现靶向 2) CAR Treg-to-APC 信号传导耐受 APC 限制同种异体反应性 T 细胞启动并促进诱导性调节性 T 细胞的产生（iTregs），它通过“感染耐受”强制执行自我维持的免疫抑制循环。如果成功，将评估小鼠同种异体移植模型中的合成串扰。平台技术可以在广泛的领域实施，以实现精确控制病理状况，包括自身免疫性疾病、移植物抗宿主病和移植排斥反应。