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
• 负责人: Xunrong Luo
• 金额: $ 27.04万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9028961
• 关键词: Acute; Affect; Allogenic; Apoptotic; Area; Autoimmunity; Autologous; Carbodiimides; Cells; Chemicals; Clinical; Clinical Trials; Coupled; Crosslinker; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Diagnosis; Disease; Donor person; Early Gene Transcriptions; Epigenetic Process; Future; Genes; Genome; Goals; Heart Transplantation; Human; Immediate-Early Genes; Immune; Immune response; Immunity; Immunosuppression; Impairment; Infection; Inflammation; Kidney; Kidney Transplantation; Knowledge; Lead; Left; Life; Literature; MS4A1 gene; Maintenance; Malignant Neoplasms; Mediating; Microbe; Modeling; Multiple Sclerosis; Murid herpesvirus 1; Mus; Myelogenous; Organ Donor; Organ Transplantation; Outcome; Peptides; Personal Communication; Phagocytes; Phagocytosis; Phenotype; Predisposition; Process; Protocols documentation; Publishing; Receptor Protein-Tyrosine Kinases; Risk; Role; Safety; Signal Transduction; Sirolimus; Splenocyte; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Transplant Recipients; Transplantation; Transplantation Tolerance; Vaccination; Virus Diseases; base; clinically relevant; cost effective; experience; graft function; heart allograft; imprint; insight; islet allograft; islet xenograft; man; microbial; migration; mouse model; nonhuman primate; novel; pathogen; prevent; programs; public health relevance; research study; response; restoration; targeted treatment; tool

 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（由申请人提供）：巨细胞病毒（CMV）血清阳性在器官捐献者和接受者中都非常普遍。在终生免疫抑制的情况下，移植后巨细胞病毒疾病是导致移植物和受者预后不良的一个重要因素。移植耐受可以完全避免免疫抑制，目前在临床上是可以实现的。在此类耐受宿主中，如何改变 CMV 感染的过程尚未得到表征。相反，并发巨细胞病毒感染如何改变耐受结果也很大程度上未知。在本申请中，我们建议使用临床高度相关的移植耐受小鼠模型来检查 CMV 感染与移植耐受之间的相互作用。在该模型中，通过移植前输送供体“阴性疫苗”来实现供体特异性耐受，该“阴性疫苗”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。我们的小鼠研究已经在非人类灵长类动物中进行了正在进行的实验，证明了这种策略对于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，确立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，我们证明急性和潜伏的 CMV 感染都会损害耐受诱导并破坏已建立的耐受性，可能是通过干扰受体酪氨酸激酶 (RTK) 介导的胞吞作用并直接或间接干扰宿主骨髓源性抑制细胞 (MDSC) 的扩增。相反，宿主中供体特异性耐受的存在会抑制潜伏 CMV 重新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（CMV 基因组表观遗传重编程的必要早期触发因素）来抑制 CMV 再激活。在本申请中，我们建议研究：（1）巨细胞病毒引起的耐受性损害的影响和机制； (2)耐受诱导抑制CMV再激活的作用和机制。我们的长期目标是确定靶向疗法，以在巨细胞病毒感染宿主中建立和维持稳定的耐受性。