Promoting Kidney Transplantation Tolerance Through Novel Immunomodulation and Cellular Therapy

通过新型免疫调节和细胞疗法提高肾移植耐受性

基本信息

批准号：
10622210
负责人：
Andrew B Adams
金额：
$ 93.59万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-20 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622210
关键词：
Acceleration Affinity Age Allografting Anti-Inflammatory Agents Antibodies Antiviral Therapy Autoimmunity Biological Products Biological Response Modifiers Bone Marrow Calcineurin inhibitor Cardiovascular Diseases Cell Therapy Cell physiology Cessation of life Chimeric Proteins Clinical Trials Development Diabetes Mellitus Dialysis procedure Disease Effector Cell End stage renal failure Environment Health Care Costs Heart Diseases Human Immune Immune Tolerance Immune response Immunity Immunosuppression Industry Infection Inflammatory Inflammatory Response Infusion procedures Innate Immune Response Kidney Transplantation Longevity Maintenance Malignant Neoplasms Memory Minority Modeling Morbidity - disease rate Myeloid Cells Myeloid-derived suppressor cells Natural Immunity OX40 Organ Organ Transplantation Outcome Pathway interactions Patient-Centered Care Patients Pharmaceutical Preparations Production Property Protocols documentation Quality of life Reagent Regimen Regulatory T-Lymphocyte Reperfusion Injury Research Personnel Role Scaffolding Protein Self Tolerance Signal Transduction Solid T cell response T-Cell Activation T-Lymphocyte TNF gene TNFRSF5 gene TNFSF4 gene TNFSF5 gene Testing Thinking Toxic effect Transplant Recipients Transplantation Transplantation Tolerance Tumor Necrosis Factor Receptor adaptive immunity antigen-specific T cells chemokine clinical translation clinically relevant cost comparison cytokine donor-specific antibody experience graft failure high risk immune checkpoint immune function immunomodulatory therapies immunoregulation improved innovation isoimmunity member mesenchymal stromal cell migration monocyte mortality risk neutrophil non-compliance nonhuman primate novel novel therapeutics premature preservation prevent response restraint safety assessment side effect transplant model

项目摘要

Transplantation is the preferred treatment for patients suffering from end-stage kidney disease. While short- term outcomes have greatly improved with the development of more effective immunosuppression, the long- term outcomes remain problematic with life-span limiting complications including a significant number of patients developing diabetes, accelerated heart disease as well as increased rates of cancers and infections. For decades transplant researchers and clinicians have sought to develop strategies to induce immune tolerance to transplanted organs and avoid the requirement for life-long immunosuppression. Transplantation tolerance is typically defined as the lack of a donor-directed immune response while preserving protective immunity in the absence of long-term immunosuppression. It is likely that any successful tolerance regimen will incorporate targeted immunosuppression strategies like costimulation blockade. Two of the most promising reagents are anti-CD154 and anti-OX40L, both of which are protolerogenic and supportive of immunoregulation as part of their mechanism of action. We have partnered with industry to evaluate two clinically relevant compounds, dazodalibep (HZN-4920) an innovative anti-CD154 nonantibody scaffold protein and a high affinity, novel anti-human OX40L antibody. In addition, we will assess the importance of the VISTA pathway on the induction of donor-specific tolerance using an agonistic anti-human VISTA antibody. VISTA has a dual role in negatively regulating antigen specific T cell responses while also impacting the innate immune response by inhibiting ischemia reperfusion injury, monocyte activation and neutrophil migration thereby suppressing the early inflammatory response. The combination of cellular therapy and costimulation blockade is a powerful strategy to promote donor-specific tolerance. Myeloid derived suppressor cells (MDSCs) have inherent immunosuppressive properties and have been used to facilitate tolerance. They modulate innate immunity and inhibit T cell activation and effector cell function while also promoting regulatory T cell expansion for maintenance of long-term donor specific tolerance. We will use donor bone marrow derived MDSCs in combination with novel therapeutics to control naïve (anti-CD154, anti-VISTA) and memory (anti-OX40L) T cell responses as well as the innate immune response (anti-VISTA) in combination with pro- tolerogenic anti-inflammatory cellular therapy (repetitive MDSC infusions). We will test this strategy in a clinically relevant nonhuman primate kidney transplant model.

移植是患有终末期肾病患者的首选治疗方法。随着更有效的免疫抑制技术的发展，长期结果已大大改善长期结局仍然存在限制寿命的并发症，包括大量的并发症患有糖尿病、加速心脏病以及癌症和感染率增加的患者。几十年来，移植研究人员和爱好者一直在寻求开发诱导免疫的策略对移植器官的耐受性并避免终生免疫抑制的需要。耐受性通常被定义为缺乏针对供体的免疫反应，同时保留保护性任何成功的耐受方案都可能在没有长期免疫抑制的情况下产生免疫力。将纳入有针对性的免疫抑制策略，例如共刺激阻断。有前景的试剂是抗 CD154 和抗 OX40L，这两种试剂均具有致耐受性并支持免疫调节作为其作用机制的一部分，我们与业界合作评估了两种。临床相关化合物，dazodalibep (HZN-4920) 是一种创新的抗 CD154 非抗体支架蛋白以及高亲和力的新型抗人 OX40L 抗体此外，我们将评估 VISTA 的重要性。使用激动性抗人 VISTA 抗体诱导供体特异性耐受的途径。具有负向调节抗原特异性 T 细胞反应的双重作用，同时也影响先天性通过抑制缺血再灌注损伤、单核细胞活化和中性粒细胞迁移来产生免疫反应从而抑制早期炎症反应。细胞疗法和共刺激的结合。阻断是促进供体特异性耐受的有效策略。 (MDSC) 具有固有的免疫抑制特性，已被用于促进耐受。调节先天免疫并抑制 T 细胞激活和效应细胞功能，同时促进调节 T 细胞扩增用于维持长期供体特异性耐受性我们将使用供体骨髓。衍生的 MDSC 与新疗法相结合，可控制幼稚（抗 CD154、抗 VISTA）和记忆（抗 OX40L）T 细胞反应以及先天免疫反应（抗 VISTA）与亲耐受性抗炎细胞疗法（重复 MDSC 输注）我们将在试验中测试该策略。临床相关的非人灵长类肾移植模型。