Overcoming humoral rejection after xenotransplantation in sensitized nonhuman primate recipients

克服致敏非人灵长类受体异种移植后的体液排斥

• 批准号: 10637942
• 负责人: Jean Kwun
• 金额: $ 81.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-06 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637942
• 关键词: Acceleration; Address; Adjuvant Therapy; Affect; Antibody Formation; Antibody Response; Antibody titer measurement; Antigens; B cell repertoire; B-Lymphocytes; Clinic; Clinical; Clinical Trials; Complement; Data; Development; Disease; Elements; End stage renal failure; Engineering; Exposure to; Family suidae; Fostering; Future; Genes; Genetic; Genetic Engineering; Goals; Graft Rejection; Graft Survival; Health; Human; Immune; Immune response; Immunity; Immunologics; Immunosuppression; Impairment; Industry Collaboration; Infection; Intervention; Kidney; Kidney Failure; Kidney Transplantation; Letters; Longevity; Lymphocyte; Macaca mulatta; Mediating; Modeling; Modification; Morbidity - disease rate; Organ; Organ Transplantation; Outcome; Patients; Phenotype; Plasma Cells; Population; Positioning Attribute; Pregnancy; Primates; Proteasome Inhibitor; Quality of life; Regimen; Risk; Skin; System; T-Lymphocyte; Testing; Therapeutic; Transfusion; Translations; Transplantation; United States; United States National Institutes of Health; Viral; Wait Time; Waiting Lists; Xenograft procedure; allograft rejection; allotransplant; anergy; antibody-mediated rejection; clinical translation; conditioning; desensitization; donor-specific antibody; efficacy evaluation; experience; first-in-human; graft failure; improved; mortality; nonhuman primate; novel; novel therapeutic intervention; post-transplant; pre-clinical; preservation; prevent; response; targeted agent; targeted treatment; transplant model; vaccine response

Abstract Xenotransplantation has long been proposed as a therapeutic strategy to address the ongoing organ shortage in transplantation. In recent years, pig-to-primate xenotransplantation outcomes have dramatically improved following advances in the genetic engineering of pig donors and utilization of costimulation blockade-based immunosuppression, such that translation to the clinic appears within reach. Highly allosensitized patients, those who have developed anti-donor antibody as a response to foreign HLA exposure, are potential first candidates for xenotransplantation given their reduced chances of undergoing allotransplantation. However, the impact of allosensitization in the setting of xenotransplantation has not yet been fully elucidated in pig-to- primate models. Our preliminary data suggest that allosensitization promotes antibody-mediated rejection (AMR) following kidney xenotransplantation and leads to early graft failure. Use of donor kidneys from highly engineered pigs prolong xenograft survival yet do not fully alleviate AMR development. Additional therapeutic strategies are thus needed to dampen the post-transplant humoral response following xenotransplantation in sensitized recipients. This project aims to evaluate novel desensitization and immunosuppression strategies to control the post-transplant humoral response and foster long-term xenograft survival in sensitized recipients. Our overarching hypothesis is that both conditioning the host immune response ahead of xenotransplantation through desensitization and continuous targeting of B cells, plasma cells, or complements following transplantation, are necessary to control the post-transplant humoral response and alter the repopulating xenoreactive immune repertoire to favor long-term graft acceptance. To explore this, we propose 3 specific aims: Specific aim 1: We will define the effects of desensitization (costimulation blockade and proteasome inhibitor) pre-transplant in rhesus monkeys undergoing kidney xenotransplantation. Specific aim 2: We will define the impact of adjuvant therapies targeting downstream elements of the humoral response following xenotransplantation. Specific aim 3: We will identify the functional phenotype of xeno-specific T and B cell repertoires required to establish long-term AMR-free xenograft survival while preserving anti-viral/vaccinal response. These advances will ultimately position us to conduct a first-in-human xenokidney transplantation in sensitized patients testing this optimized immunosuppressive regimen. Our proposal involves many academic and industry collaborations that are ongoing as attested by letters of support. The impact of this proposal has broad implications that may benefit U.S. citizens affected by end stage renal failure or by immune-mediated illnesses or infections.

抽象的 长期以来一直提出异种移植作为解决持续器官短缺的治疗策略 在移植中。近年来，猪到顶峰的异种移植结果已显着改善 随后猪捐赠者的基因工程进展并利用了基于结局的封锁 免疫抑制，使转化为诊所的转换似乎可以触及。高度敏感的患者， 那些开发了抗唐纳抗体作为对外国HLA暴露的反应的人，这是潜在的 异种移植的候选者鉴于其进行同种异体移植的机会减少。然而， 在异种移植中的敏感性影响尚未完全阐明 灵长类动物模型。我们的初步数据表明，敏敏化促进了抗体介导的排斥反应 （AMR）肾脏异种移植后，导致早期移植失败。高度使用供体肾脏 工程猪延长了异种移植的存活，但不能完全减轻AMR的发展。其他治疗性 因此，需要策略来抑制移植后移植后的体液反应。 灵敏的接受者。该项目旨在评估新颖的脱敏和免疫抑制策略 控制移植后的体液反应并促进敏化受体中的长期异种移植存活。 我们的总体假设是，在异种移植之前调节宿主免疫反应 通过脱敏和连续靶向B细胞，浆细胞或以下补充 移植是控制移植后的体液反应并改变重新流动所必需的 异种反应性免疫曲目有利于长期移植物接受。为了探索这一点，我们提出了3个特定的 目的：特定目的1：我们将定义脱敏的影响（contimulation封锁和蛋白酶体 抑制剂）在恒河猴进行肾脏异种移植的恒河猴中移植。特定目标2：我们将 定义针对体液反应下游元素的辅助疗法的影响 异种移植。特定目标3：我们将确定异种特异性T和B细胞的功能表型 建立长期无AMR异种移植物存活所需的曲目，同时保存抗病毒/疫苗 回复。这些进步最终将使我们在human Xenokidney进行中 敏化的患者测试该优化的免疫抑制方案。我们的建议涉及许多学术 以及由支持信证明的行业合作。该提议的影响有 可能受益于受末期肾衰竭或免疫介导的美国公民受益的广泛含义 疾病或感染。