Advancing Transplantation Tolerance in Nonhuman Primates

提高非人类灵长类动物的移植耐受性

基本信息

批准号：
10622205
负责人：
Andrew B Adams
金额：
$ 363.53万
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/10622205
关键词：
ATAC-seq Acceleration Address Antibodies Apoptotic Autoimmune Diseases Bone Marrow Bone Marrow Stem Cell Transplantation CD8-Positive T-Lymphocytes Cardiovascular Diseases Cell Therapy Cell physiology Cells Chronic Collaborations Data Development Diabetes Mellitus Disease Effector Cell Elements End stage renal failure Environment Fertilization Fingerprint Goals Health Heart Diseases Human ITGAM gene Immune Immune Tolerance Immune response Immunosuppression Infection Inflammasome Inflammation Inflammatory Response Innate Immune Response Interleukin-1 Kidney Transplantation Leukocytes Maintenance Malignant Neoplasms Mediating Memory Modeling Morbidity - disease rate Myeloid Cells Myeloid-derived suppressor cells Nanotechnology Natural Immunity OX40 Organ Organ Transplantation Outcome Pathway interactions Patients Personal Satisfaction Pharmaceutical Preparations Phase Property Publications Publishing Reagent Regenerative Medicine Regimen Regulatory T-Lymphocyte Reperfusion Injury Research Research Personnel Role Signal Transduction Solid System T cell response T memory cell T-Cell Activation T-Lymphocyte TNFRSF5 gene TNFSF4 gene TNFSF5 gene Techniques Testing Therapeutic Tissues Transplant Recipients Transplantation Transplantation Tolerance adaptive immune response adaptive immunity antigen-specific T cells clinical application clinically relevant design digital immunoregulation improved industry partner innovation insight interest isoimmunity migration monocyte mortality nanoparticle delivery neutrophil next generation nonhuman primate novel novel strategies novel therapeutics prevent programs prospective receptor response side effect synergism therapeutic target transcriptome sequencing

项目摘要

While short-term outcomes following organ transplant have greatly improved with the development of more effective immunosuppression, long-term outcomes remain problematic with 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. It is likely that any successful tolerance regimen will incorporate targeted immunosuppression strategies like costimulation blockade. One of the most important interactions is the CD40-CD154 pathway. We will evaluate novel, clinically relevant therapeutics targeting either CD40 or CD154 and explore their role in facilitating tolerance. Based on our recent publication showing that CD11b is a novel alternate receptor for CD154 during alloimmunity, we will also test novel nanotechnology to block the CD154:CD11b interaction, an important mechanism of cross-talk between the innate and adaptive immune responses during transplantation. Moreover, based on our published data showing that memory T cells are a potent barrier to transplantation tolerance, we will determine the role of OX40-OX40L blockade to control alloreactive memory CD8+ T cells and promote a pro-regulatory environment. 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. We will also investigate the contribution of IL-1 and the inflammasome on tolerance induction and employ clinically applicable therapeutics to control early inflammation during the induction of tolerance. 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. Apoptotic donor leukocytes (ADLs) represent another promising cellular therapy that has been proven to control alloreactive T cells and promote donor specific T cell deletion. We will use donor bone marrow derived MDSCs or ADLs in combination with the above novel therapeutics to promote tolerance in nonhuman primate kidney transplantation.

虽然随着更多技术的发展，器官移植后的短期结果已大大改善有效的免疫抑制，对相当多的患者来说，长期结果仍然存在问题患糖尿病、加速心脏病以及增加癌症和感染的发病率。几十年来，移植研究人员和讲坛一直在寻求开发诱导免疫耐受的策略移植器官并避免终生免疫抑制的需要。成功的耐受方案将结合有针对性的免疫抑制策略，例如共刺激最重要的相互作用之一是 CD40-CD154 途径。针对 CD40 或 CD154 的临床相关疗法，并探索它们在促进耐受性中的作用。根据我们最近发表的文章，表明 CD11b 是 CD154 的一种新型替代受体同种免疫，我们还将测试新颖的纳米技术来阻断 CD154:CD11b 相互作用，这是一种重要的相互作用移植过程中先天性免疫反应和适应性免疫反应之间的串扰机制。此外，根据我们发表的数据显示记忆 T 细胞是移植的潜在障碍耐受性，我们将确定 OX40-OX40L 阻断在控制同种反应性记忆 CD8+ T 细胞中的作用，此外，我们将评估 VISTA 途径对监管的重要性。使用激动性抗人 VISTA 抗体诱导供体特异性耐受具有双重作用。负调节抗原特异性 T 细胞反应，同时还通过以下方式影响先天免疫反应：抑制缺血再灌注损伤、单核细胞活化和中性粒细胞迁移，从而抑制我们还将研究 IL-1 和炎症小体对早期炎症反应的贡献。耐受诱导并采用临床适用的治疗方法来控制治疗期间的早期炎症细胞疗法和共刺激阻断的结合是诱导耐受的有效策略。促进供体特异性耐受性。它们具有免疫抑制特性，并已被用于促进耐受性。抑制 T 细胞活化和效应细胞功能，同时促进调节性 T 细胞扩增维持长期供体特异性耐受性是另一个例子。有前途的细胞疗法已被证明可以控制同种异体反应性 T 细胞并促进供体特异性 T 细胞我们将使用供体骨髓来源的 MDSC 或 ADL 与上述新型药物相结合。促进非人灵长类肾移植耐受性的治疗方法。