Advancing Transplantation Tolerance in Nonhuman Primates

提高非人类灵长类动物的移植耐受性

• 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
• 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

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.

虽然器官移植后的短期结果已经大大改善， 有效的免疫抑制，长期的结果仍然是有问题的大量患者 发展糖尿病，加速心脏病以及增加癌症和感染率。为 几十年来，移植研究人员和临床医生一直在寻求开发诱导免疫耐受的策略 移植器官，避免终身免疫抑制的要求。很可能任何 成功耐受方案将结合靶向免疫抑制策略，如共刺激 封锁最重要的相互作用之一是CD 40-CD 154途径。我们将评估小说， 靶向CD 40或CD 154的临床相关治疗，并探索其在促进耐受性中的作用。 基于我们最近的出版物显示，CD 11b是CD 154的一种新的替代受体， 我们还将测试新的纳米技术来阻断CD 154：CD 11b相互作用，这是一种重要的 移植过程中先天性和适应性免疫应答之间的相互作用机制。 此外，根据我们发表的数据显示，记忆T细胞是移植的有效屏障， 我们将确定OX 40-OX 40 L阻断对控制同种异体反应性记忆CD 8 + T细胞的作用， 促进有利于监管的环境。此外，我们还将评估VISTA通路对 使用激动性抗人VISTA抗体诱导供体特异性耐受。VISTA具有双重作用， 负调节抗原特异性T细胞应答，同时还通过以下方式影响先天免疫应答： 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 早期炎症反应。我们还将研究IL-1 β和炎性小体在炎症反应中的作用。 免疫耐受诱导，并采用临床上适用的治疗方法来控制免疫耐受期间的早期炎症。 诱导耐受性。细胞治疗和共刺激阻断的组合是一种强有力的策略， 促进捐助者的具体耐受性。髓源性抑制细胞（MDSC）具有固有的 免疫抑制特性，并已用于促进耐受性。它们调节先天免疫， 抑制T细胞活化和效应细胞功能，同时还促进调节性T细胞扩增， 维持长期供体特异性耐受。凋亡供体白细胞（ADL）代表另一种 已被证明控制同种异体反应性T细胞并促进供体特异性T细胞增殖的有前景的细胞疗法 删除。我们将使用供体骨髓来源的MDSC或ADL与上述新的MDSC或ADL组合。 在非人灵长类动物肾移植中促进耐受性的治疗剂。