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：
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
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

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

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（由适用提供）：在器官捐献者和受体中，巨细胞病毒（CMV）均高度普遍存在。在终生的免疫抑制下，移植后CMV疾病是贫困和受体结果的重要原因。移植耐受性可以完全避免免疫抑制，现在在临床上成功。在这种耐受性宿主中，如何修改CMV感染的过程尚未被表征。相反，并发CMV感染如何改变耐受性的结果也在很大程度上未知。在此应用中，我们建议使用高度临床相关的移植耐受模型来检查CMV感染和移植耐受性之间的相互相互作用。在该模型中，通过移植前递送供体的“阴性疫苗”的供体特异性耐受性可实现，这些供体“负疫苗”由用交联1-乙基-3-（3-二甲基氨基丙基）-Carbodiiimide（ECDI）处理的供体细胞组成。我们的鼠研究已经导致了非人类素数的持续实验，证明了这种策略对同种异体和异种耐受性诱导的有效性。更重要的是，我们的同事最近使用ECDI固定肽偶联自体细胞进行了多发性硬化症，发布了一项人工临床试验，确立了这种新型耐受性策略的可行性，安全性和效率。在此模型中，我们使用鼠CMV，证明急性和潜在的CMV感染损害耐受性诱导并破坏了既定的耐受性，这可能是通过干扰受体酪氨酸激酶（RTK）介导的效率的效率，直接或直接或间接地干扰宿主糖基质抑制细胞的扩张（MDSC）。相反，宿主中供体特异性耐受性的存在会立即抑制（IE）基因转录，这是潜在的CMV重新激活所必需的。基于这些发现，我们假设CMV感染通过破坏RTK介导的宿主细胞与ECDI固定供体细胞之间的耐受性相互作用来损害耐受性，而相反的耐受性通过抑制移植诱导的感染，是一种强制性的早期触发器，对CMV基因组抑制了CMV重新激活CMV。在此应用中，我们建议检查：（1）CMV诱导的耐受性障碍的影响和机制；（2）耐受性诱导的CMV重新激活的效果和机制。我们的长期目标是定义针对CMV感染宿主中稳定耐受性的有针对性疗法。