Modeling concurrent cytomegalovirus infection and transplantation tolerance

模拟巨细胞病毒并发感染和移植耐受

基本信息

  • 批准号:
    9240574
  • 负责人:
  • 金额:
    $ 27.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-03-15 至 2021-02-28
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) seropositivity is highly prevalent among both organ donors and recipients. Under life-long immunosuppression, post-transplant CMV disease is a significant contributor to poor graft and recipient outcome. Transplant tolerance allows complete avoidance of immunosuppression and is now clinically achievable. In such tolerant hosts, how the course of CMV infection may be modified has not been characterized. Conversely, how concurrent CMV infection may alter the outcome of tolerance is also largely unknown. In this application, we propose to examine the reciprocal interaction between CMV infection and transplant tolerance, using a highly clinically relevant murine model of transplant tolerance. In this model, donor-specific tolerance is achieved by pre-transplant delivery of donor "negative vaccination" consisting of donor cells treated with a crosslinker 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI). Our murine studies have already led to ongoing experiments in non-human primates, demonstrating promising efficacy of this strategy for both allogeneic and xenogeneic tolerance induction. More importantly, our colleagues recently published a first-in-man clinical trial using ECDI-fixed peptide-coupled autologous cells for multiple sclerosis, establishing the feasibility, safety and efficacy of this novel tolerance strategy. Using murine CMV in this model, we demonstrate that both acute and latent CMV infection impair tolerance induction and destabilize established tolerance, likely via interfering with Receptor Tyrosine Kinase (RTK)-mediated efferocytosis and directly or indirectly interfering with expansion of host myeloid derived suppressor cells (MDSCs). Conversely, presence of donor-specific tolerance in the host suppresses immediate early (IE) gene transcription necessary for latent CMV reactivation. Based on these findings, we hypothesize that CMV infection impairs tolerance via disrupting RTK-mediated tolerogenic interaction between host cells and ECDI-fixed donor cells, and conversely tolerance inhibits CMV reactivation via inhibiting transplant-induced inflammation, an obligatory early triggers for CMV genome epigenetic reprogramming. In this application, we propose to examine: (1) the effects and mechanisms of CMV-induced tolerance impairment; (2) the effects and mechanisms of tolerance-induced inhibition of CMV reactivation. Our long-term goal is to define targeted therapies for establishing and maintaining stable tolerance in hosts with CMV infection.
 描述(由申请方提供):巨细胞病毒(CMV)血清阳性在器官供体和受体中均高度流行。在终身免疫抑制下,移植后CMV疾病是移植物和受体结局不良的重要因素。移植耐受可以完全避免免疫抑制,现在临床上可以实现。在这种耐受宿主中,CMV感染的过程如何改变尚未被表征。相反,并发的巨细胞病毒感染如何改变耐受性的结果在很大程度上也是未知的。在本申请中,我们建议使用高度临床相关的移植耐受小鼠模型来研究CMV感染和移植耐受之间的相互作用。在该模型中,供体特异性耐受通过移植前递送供体“阴性疫苗接种”来实现,所述供体“阴性疫苗接种”由用交联剂1-乙基-3-(3-二甲基氨基丙基)-碳二亚胺(ECDI)处理的供体细胞组成。我们的鼠研究已经导致在非人灵长类动物中进行的实验,证明了这种策略对同种异体和异种耐受诱导的有希望的功效。更重要的是,我们的同事最近发表了一项使用ECDI固定的肽偶联自体细胞治疗多发性硬化症的首次人体临床试验,确定了这种新型耐受策略的可行性,安全性和有效性。在该模型中使用小鼠CMV,我们证明了急性和潜伏CMV感染都损害耐受诱导并使已建立的耐受不稳定,这可能是通过干扰受体酪氨酸激酶(RTK)介导的巨噬细胞增多和直接或间接干扰宿主髓源性抑制细胞(MDSC)的扩增。相反,宿主中供体特异性耐受的存在抑制了潜伏CMV再激活所必需的立即早期(IE)基因转录。基于这些发现,我们假设CMV感染通过破坏宿主细胞和ECDI固定的供体细胞之间RTK介导的致耐受性相互作用来损害耐受性,相反,耐受性通过抑制移植诱导的炎症来抑制CMV再活化,这是CMV基因组表观遗传重编程的强制性早期触发因素。在本申请中,我们拟研究:(1)CMV诱导的耐受性损害的作用和机制;(2)耐受性诱导的CMV再激活抑制的作用和机制。我们的长期目标是确定在CMV感染宿主中建立和维持稳定耐受性的靶向治疗。

项目成果

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Xunrong Luo其他文献

Xunrong Luo的其他文献

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{{ truncateString('Xunrong Luo', 18)}}的其他基金

Donor Kidney Resident Macrophages in Kidney Allograft Early Inflammation and Alloimmunity
肾同种异体移植早期炎症和同种免疫中的供肾驻留巨噬细胞
  • 批准号:
    10467170
  • 财政年份:
    2022
  • 资助金额:
    $ 27.04万
  • 项目类别:
Donor Kidney Resident Macrophages in Kidney Allograft Early Inflammation and Alloimmunity
肾同种异体移植早期炎症和同种免疫中的供肾驻留巨噬细胞
  • 批准号:
    10588212
  • 财政年份:
    2022
  • 资助金额:
    $ 27.04万
  • 项目类别:
Therapeutics Development Core (Core B)
治疗开发核心(核心B)
  • 批准号:
    10203939
  • 财政年份:
    2018
  • 资助金额:
    $ 27.04万
  • 项目类别:
Therapeutics Development Core (Core B)
治疗开发核心(核心B)
  • 批准号:
    10460933
  • 财政年份:
    2018
  • 资助金额:
    $ 27.04万
  • 项目类别:
Determinants of donor-specific T cell tolerance in kidney transplantation in non-sensitized recipients
非致敏受者肾移植中供体特异性 T 细胞耐受的决定因素
  • 批准号:
    10622059
  • 财政年份:
    2017
  • 资助金额:
    $ 27.04万
  • 项目类别:
Modeling concurrent cytomegalovirus infection and transplantation tolerance
模拟巨细胞病毒并发感染和移植耐受
  • 批准号:
    9028961
  • 财政年份:
    2016
  • 资助金额:
    $ 27.04万
  • 项目类别:
Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy
用于细胞替代疗法的蛋白质释放微孔支架
  • 批准号:
    9302428
  • 财政年份:
    2010
  • 资助金额:
    $ 27.04万
  • 项目类别:
Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy
用于细胞替代疗法的蛋白质释放微孔支架
  • 批准号:
    8886518
  • 财政年份:
    2010
  • 资助金额:
    $ 27.04万
  • 项目类别:
ECDI Coupled Cells for Tolerance in Allogeniec Islet Cell Transplantation for T1D
ECDI 偶联细胞在 T1D 异体胰岛细胞移植中的耐受性
  • 批准号:
    8001130
  • 财政年份:
    2010
  • 资助金额:
    $ 27.04万
  • 项目类别:
Clinical Islet Transplantation at Northwestern
西北大学临床胰岛移植
  • 批准号:
    7941899
  • 财政年份:
    2009
  • 资助金额:
    $ 27.04万
  • 项目类别:

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