The Role of CD28 cosignaling molecules on anti-viral immune responses in Chronic Kidney Disease
CD28 共信号分子在慢性肾脏病抗病毒免疫反应中的作用
基本信息
- 批准号:9759637
- 负责人:
- 金额:$ 6.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-05 至 2020-08-04
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsAntibodiesAntiviral AgentsAntiviral ResponseB Cell ProliferationB lymphoid malignancyBK VirusBindingCD28 geneCD8-Positive T-LymphocytesCD80 geneCD86 geneCD8B1 geneCTLA4 geneCTLA4-IgCalcineurin inhibitorChronic Kidney FailureClinicalCytomegalovirusDataDevelopmentDiseaseEquilibriumFDA approvedFamily memberFoundationsGenerationsGraft RejectionHomologous GeneHuman Herpesvirus 4ImmuneImmune responseImmune systemImmunityImmunologic SurveillanceImmunosuppressionImpairmentIndividualInfectionInflammationLymphoproliferative DisordersMaintenanceMalignant NeoplasmsMediatingMurid herpesvirus 1MusPPP3CA genePathway interactionsPatientsPredispositionPublishingReagentRecrudescencesRoleSignal PathwaySignal TransductionT cell responseT-Cell ActivationT-Cell ProliferationT-LymphocyteTacrolimusTimeToxic effectTransplantationVaccinesViralViral Load resultVirusVirus DiseasesWorkadaptive immune responseantiviral immunityattenuationbaseexperimental studygraft functionimmune activationimmunoregulationimprovedinfected B cellinhibitor/antagonistinsightnovelnovel therapeuticspost-transplantpreservationpreventprogrammed cell death ligand 1receptorresponsetraining opportunity
项目摘要
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.
摘要
限制移植后免疫介导的损伤,同时保持保护性免疫
需要精确调节免疫系统一个主要的挑战是同种异体反应性T细胞的激活,
淋巴细胞,这是仔细控制的平衡,共刺激和共抑制信号T
细胞接收。CD 28/CTLA-4途径是T细胞中的原型共信号传导途径,其中CTLA-4
共抑制作为CD 28共刺激的反信号,因为它们结合相同的受体CD 80
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。
在移植环境中不适当的T细胞活化。Belatacept与CD 80/86结合,
第一个共刺激阻滞剂被FDA批准用于临床移植,
与钙调磷酸酶抑制剂(CNI)相比,改善了长期移植功能,毒性更低。使用
贝拉西普与EB病毒相关的移植后淋巴增生性淋巴结转移的发生率增加有关。
疾病(PTLD),这是通常保持在严格的控制下的免疫监视活动,
病毒特异性CD 8 + T细胞。CD 28介导的信号是足够的EBV特异性免疫所必需的,
CD 8 + T细胞应答和病毒复发的控制最近受到质疑。最近的两
研究表明,阻断CD 28与阻断CD 80/CD 86是根本不同的,
关于EBV特异性适应性免疫应答和病毒控制。最近,一种选择性地
靶向CD 28,同时保持CTLA-4介导的抑制完整。这些抗CD 28
结构域抗体已经显示出比贝拉西普针对CD 86-
与CTLA-4相比,它可以驱动T细胞增殖,并成为更有效的移植物排斥抑制剂
IG治疗。考虑到抗CD 28 dAb的强效免疫抑制作用,
选择性CD 28阻断对保护性免疫影响是一个重要的临床问题。此外,本发明还
这种比较从未在移植前慢性肾病(CKD)的情况下进行过,
哪些患者有充分记录的免疫失调,导致对
感染、免疫激活相关炎症和对疫苗的不良反应。为此我们
计划直接比较选择性CD 28阻断与CTLA-4 IG对保护性免疫的影响
小鼠巨细胞病毒(CMV)和MHV-68(EBV的小鼠同源物)的应答,
健康WT小鼠和受CKD影响的小鼠。确定CD 28与CD 80/86的精确效应
阻断CMV和MHV特异性CD 8 + T细胞的产生、维持和功能
在这些环境中的反应将提供机制的见解,并告知新的选择性的发展。
用于临床移植的CD 28阻断剂。
项目成果
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