Advancing Transplantation Tolerance in Nonhuman Primates

虽然器官移植后的短期结果随着更多的 有效的免疫抑制，长期结果对相当数量的患者来说仍然是个问题 罹患糖尿病、加速心脏病以及癌症和感染率的增加。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。很可能有任何 成功的耐受方案将包括有针对性的免疫抑制策略，如协同刺激 封锁。其中最重要的相互作用是CD40-CD154途径。我们将评估小说， 以CD40或CD154为靶点的临床相关疗法，并探讨它们在促进耐受中的作用。 根据我们最近发表的文章显示，CD11b是CD154的一个新的替代受体 在同种异体免疫中，我们还将测试新的纳米技术来阻断CD154：CD11b的重要相互作用 移植过程中先天免疫反应和获得性免疫反应之间的串扰机制。 此外，根据我们公布的数据显示，记忆T细胞是移植的有效障碍 耐受性，我们将确定OX40-OX40L阻断在控制同种异体反应性记忆CD8+T细胞和 营造有利于监管的环境。此外，我们将评估Vista途径在 用激动型抗人VistA抗体诱导供体特异性耐受。Vista在以下方面具有双重作用 负性调节抗原特异性T细胞反应，同时也影响先天免疫反应 抑制缺血再灌注损伤、单核细胞活化和中性粒细胞迁移，从而抑制缺血再灌注损伤。 早期炎症反应。我们还将研究IL-1和炎症小体在体内的作用。 诱导耐受并采用临床适用的治疗方法控制早期炎症 诱导耐受性。细胞治疗和共刺激阻断的结合是一种强有力的策略 促进特定供者的耐受性。髓系来源的抑制细胞(MDSCs)具有固有的 具有免疫抑制特性，并已用于促进耐受性。它们调节先天免疫力， 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 长期供体特异性耐受性的维持。凋亡的供者白细胞(ADL)是另一种 有希望的细胞疗法，已被证明控制同种异体反应性T细胞和促进供者特异性T细胞 删除。我们将使用供体骨髓来源的MDSCs或ADL与上述新的 促进非人类灵长类肾移植耐受性的治疗方法。

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.