Promoting Kidney Transplantation Tolerance Through Novel Immunomodulation and Cellular Therapy

移植是终末期肾病患者的首选治疗方法。虽然时间很短- 随着更有效的免疫抑制的发展，长期结果大大改善， 足月结局仍然有问题，有限制寿命的并发症，包括相当数量的 患糖尿病、心脏病加速以及癌症和感染率增加的患者。 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的策略 对移植器官的耐受性，避免终身免疫抑制的要求。移植 耐受通常被定义为缺乏供体定向的免疫反应，同时保持保护性 在没有长期免疫抑制的情况下产生免疫力。很可能任何成功的耐受养生法 将纳入有针对性的免疫抑制策略，如共刺激阻断。其中最多的两个 有希望的试剂是抗CD154和抗OX40L，这两种试剂都是前耐受的，都支持 免疫调节是其作用机制的一部分。我们已经与业界合作评估了两个 临床相关化合物Dazodalibep(HZN-4920)--一种新型的抗CD154非抗体支架蛋白 和高亲和力的新型抗人OX40L抗体。此外，我们还将评估Vista的重要性 激动型抗人VistA抗体诱导供体特异性耐受的途径。Vista 在负调节抗原特异性T细胞反应方面具有双重作用，同时也影响先天的 抑制缺血再灌注损伤、单核细胞活化和中性粒细胞迁移的免疫反应 从而抑制早期的炎症反应。细胞治疗与共刺激的结合 封锁是促进针对捐赠者的耐受性的一种强有力的战略。髓系来源的抑制细胞 (MDSCs)具有固有的免疫抑制特性，并已被用于促进耐受。他们 调节先天免疫，抑制T细胞活化和效应细胞功能，同时促进调节 T细胞扩增用于维持长期供者特异性耐受。我们将使用捐献的骨髓 衍生MDSCs联合新疗法控制幼稚(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PRO- 耐受性抗炎细胞疗法(重复输注MDSC)。我们将在一个 临床相关的非人灵长类肾脏移植模型。

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.