The Role of CD28 cosignaling molecules on anti-viral immune responses in Chronic Kidney Disease

摘要 在维持保护性免疫的同时限制移植后的免疫介导性损害 需要对免疫系统进行精确的调节。一个主要的挑战是同种异体反应T细胞的激活 淋巴细胞，它受到共刺激和共抑制信号T的平衡的小心控制 细胞接收。CD28/CTLA-4通路是T细胞中典型的共信号通路，与CTLA-4 共抑制作为CD28共刺激的反信号，因为它们与相同的受体CD80结合 和CD86。通过阻断这一途径进行免疫调节是一种很有前途的预防方法 移植过程中T细胞的不适当激活。Belatacept与CD80/86绑定，是 首个协同刺激阻滞剂被FDA批准用于临床移植，并提供了显著的 与钙调神经磷酸酶抑制剂(CNI)相比，改善了长期移植物功能并减少了毒性。使用 贝拉西普与移植后EB病毒相关淋巴增殖性疾病的发生率增加有关 疾病(PTLD)，通常由免疫监视活动严格控制 病毒特异性CD8+T细胞。认为CD28介导的信号是足够的EBV特异性所必需的 CD8+T细胞的反应和病毒复发的控制最近受到了质疑。最近的两个 研究表明，阻断CD28与阻断CD80/CD86有根本的不同 关于EBV特异性适应性免疫反应和病毒控制。最近，有一种试剂选择性地 靶点CD28在保持CTLA-4介导的抑制作用不变的同时，已经被开发出来。这些抗CD28抗体 已经证明，针对CD86的区域抗体的效力大约是贝拉塔塞特的5倍- 促进T细胞增殖，并成为比CTLA-4更有效的移植排斥反应抑制因子 免疫球蛋白治疗。鉴于抗CD28 DAb具有强大的免疫抑制作用，请理解 选择性阻断CD28对保护性免疫的影响是一个重要的临床问题。另外， 这种比较从来没有在移植前慢性肾脏疾病(CKD)的环境中进行过 哪些患者有充分的证据表明免疫失调会增加其易感性 感染、与免疫激活相关的炎症以及对疫苗的不良反应。为此，我们 计划直接比较选择性CD28阻断和CTLA-4免疫球蛋白在保护性免疫中的作用 对小鼠巨细胞病毒(CMV)以及EBV的小鼠同源物MHV-68的应答 无论是健康的WT小鼠还是CKD的小鼠。确定CD28与CD80/86的确切效果 阻断CMV和MHV特异性CD8+T细胞的产生、维持和功能 在这些背景下的回应将提供机械性的洞察，并为新的选择性的发展提供信息 用于临床移植的CD28阻滞剂。

Abstract Limiting immune-mediated damage following transplantation while maintaining protective immunity requires precise regulation of the immune system. A major challenge is the activation of alloreactive T lymphocytes, which is carefully controlled by the balance of costimulatory and coinhibitory signals T cells receive. The CD28/CTLA-4 pathway is the prototypic co-signaling pathway in T cells, with CTLA-4 co-inhibition acting as the counter-signal to CD28 costimulation as they bind the same receptors, CD80 and CD86. Immunomodulation via blockade of this pathway is a promising approach to prevent inappropriate T cell activation in the setting of transplantation. Belatacept, which binds to CD80/86, is the first costimulation blocker to be FDA approved for use in clinical transplantation and offers significantly improved long-term graft function and fewer toxicities compared to calcineurin inhibitors (CNIs). Use of Belatacept was associated with increased rates of EBV-associated post-transplant lymphoproliferative disorder (PTLD), which is normally kept under strict control by the immune surveillance activities of virus-specific CD8+ T cells. The idea that CD28-mediated signals are required for sufficient EBV-specific CD8+ T cell responses and control of viral recrudescence has recently come into question. Two recent studies have suggested that blocking CD28 is fundamentally different than blocking CD80/CD86 with regard to EBV-specific adaptive immune responses and viral control. Recently, a reagent that selectively targets CD28, while leaving CTLA-4-mediated inhibition intact, has been developed. These anti-CD28 domain antibodies have been shown to be roughly five times more potent than Belatacept against CD86- driven T cell proliferation and to be a more potent inhibitor of graft rejection when compared to CTLA-4 Ig treatment. Given the potent immunosuppressive effects of the anti-CD28 dAb, understanding the impact of selective CD28 blockade on protective immunity is an important clinical question. Additionally, this comparison has never been made in the setting of pre-transplant chronic kidney disease (CKD) in which patients have a well-documented immune dysregulation leading to increased susceptibility to infections, immune-activation-associated inflammation, and poor responses to vaccines. To this end, we plan to directly compare the effects of selective CD28 blockade vs. CTLA-4 Ig on protective immune responses to both murine cytomegalovirus (CMV) as well as MHV-68, a murine homolog of EBV, in both healthy WT mice and mice affected by CKD. Determining the precise effects of CD28 vs. CD80/86 blockade on the generation, maintenance, and functionality of CMV- and MHV-specific CD8+ T cell responses in these settings will provide mechanistic insight and inform the development of novel selective CD28 blockers for use in clinical transplantation.