Innate Immunity and Viral Renal Allograft Injury

先天免疫和病毒性同种异体肾移植损伤

• 批准号: 9319116
• 负责人: Masako Shimamura
• 金额: $ 37.38万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-08 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319116
• 关键词: Activated Natural Killer Cell; Acute; Adult; Allografting; Animal Model; Animals; Archives; Biopsy; Blood; Cell Transplants; Cessation of life; Characteristics; Childhood; Clinical; Cytomegalovirus; Cytomegalovirus Infections; Databases; Development; Epidemiology; Event; Exhibits; Future; Ganciclovir; Graft Rejection; Human; Immunity; Immunosuppression; Infection; Inferior; Injury; Intervention; Investigation; Kidney Failure; Kidney Transplantation; Link; Longevity; Mediating; Memory; Modeling; Monitor; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Organ Donor; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Population; Prophylactic treatment; Quality of life; Role; Schedule; Specimen; Testing; Translating; Transplant Recipients; Transplantation; Viral; Viremia; Virus; Virus Diseases; Virus Replication; antiviral immunity; clinical care; clinical phenotype; clinically relevant; defined contribution; experience; graft function; human disease; human subject; improved; improved outcome; kidney allograft; mouse model; patient population; pediatric patients; peripheral blood; prognostic; prospective; public health relevance; success

DESCRIPTION (provided by applicant): Despite advances in immunosuppression, renal allograft survival remains limited to about 10 years. This is particularly important in pediatric patients due to their expected lifespans compared to adults (whose outcome most often is death with a functioning graft). In numerous studies, human cytomegalovirus (HCMV) infection has been associated with inferior transplant outcome which is improved by ganciclovir prophylaxis, but the mechanisms underlying these observations remain cryptic. The pathogenesis of CMV mediated allograft injury is important because viral allograft injury may be potentially modifiable to improve transplant survival. HCMV infection is associated with natural killer (NK) cell activation and acute rejection in renal transplant patients. NK cell activation itself also correlaes with acute and late rejection, but a direct association between HCMV, NK cells, and transplant outcome has not yet been defined. These findings are recapitulated in a nontolerant murine renal transplant model of rejection, with both NK infiltrates and acute rejection intensified in murine CMV (MCMV) infected allografts. Ganciclovir reduces NK infiltrates and improves graft damage in the murine model, resembling improved outcome in patients receiving ganciclovir prophylaxis. In the animal model, NK depletion reduces MCMV associated damage, supporting a direct role of NK cells in viral allograft injury. Thus, both human transplant populations and th murine renal transplant model exhibit remarkably similar findings supporting a pathogenic role of NK cells in CMV induced allograft injury. We will use this model to define mechanisms of MCMV induced NK activation in renal transplantation, followed by manipulations of these host and viral parameters of NK activation to modulate viral allograft injury. Such studies are essential to identify potential pathways that can be modified by clinical interventions to ameliorate viral allograft injury, yet cannot be performed in human subjects. However, given the limitations of animal models in precise recapitulation of human disease, we will expand the relevance of the animal model intragraft findings by analyzing NK activation in clinical allograft biopsies from a population of pediatric renal transplant recipients, then correlating the biopsy findings with HCMV infection, peripheral blood NK activation, and graft outcome in these patients. Understanding the pathogenesis of CMV associated allograft injury using both the animal model and a relevant patient population offers what we believe is the most promising approach for the development of strategies to improve transplant survival for HCMV infected patients.

描述（由申请人提供）：尽管免疫抑制方面取得了进展，同种异体肾移植物的存活率仍然限于约 10 年。这对于儿科患者尤其重要，因为与成人相比，他们的预期寿命更长（其结果通常是移植功能正常的死亡）。在许多研究中，人巨细胞病毒（HCMV）感染与较差的移植结果相关，通过更昔洛韦预防可以改善移植结果，但这些观察结果背后的机制仍然神秘。 CMV 介导的同种异体移植物损伤的发病机制很重要，因为病毒同种异体移植物损伤可能是可改变的 以提高移植存活率。 HCMV 感染与肾移植患者的自然杀伤 (NK) 细胞激活和急性排斥反应有关。 NK 细胞激活本身也与急性和晚期排斥反应相关，但 HCMV、NK 细胞和移植结果之间的直接关系尚未确定。这些发现在不耐受的小鼠肾移植排斥模型中得到了重现，在小鼠 CMV (MCMV) 感染的同种异体移植物中，NK 浸润和急性排斥反应均加剧。在小鼠模型中，更昔洛韦可减少 NK 浸润并改善移植物损伤，类似于接受更昔洛韦预防治疗的患者的预后改善。在动物模型中，NK 耗竭减少了 MCMV 相关损伤，支持 NK 细胞在病毒同种异体移植损伤中的直接作用。因此，人类移植群体和鼠肾移植模型都表现出非常相似的发现，支持 NK 细胞在 CMV 诱导的同种异体移植物损伤中的致病作用。我们将使用该模型来定义肾移植中 MCMV 诱导 NK 激活的机制，然后操纵这些 NK 激活的宿主和病毒参数来调节病毒同种异体移植物损伤。此类研究对于确定可以通过临床干预来改善病毒同种异体移植物损伤的潜在途径至关重要，但不能在人类受试者中进行。然而，考虑到动物模型在精确再现人类疾病方面的局限性，我们将通过分析儿科肾移植受者群体临床同种异体移植物活检中的 NK 激活，然后将活检结果与 HCMV 相关联，扩大动物模型移植物内发现的相关性这些患者的感染、外周血 NK 激活和移植结果。使用动物模型和相关患者群体了解 CMV 相关同种异体移植损伤的发病机制，为制定提高 HCMV 感染患者移植存活率的策略提供了最有前途的方法。

项目成果

Murine cytomegalovirus promotes renal allograft inflammation via Th1/17 cells and IL-17A.

鼠巨细胞病毒通过 Th1/17 细胞和 IL-17A 促进肾同种异体移植物炎症。

• 发表时间: 2022-10
• 作者: Dhital, Ravi;Anand, Shashi;Graber, Brianna;Zeng, Qiang;Velazquez, Victoria M;Boddeda, Srinivasa R;Fitch, James R;Minz, Ranjana W;Minz, Mukut;Sharma, Ashish;Cianciolo, Rachel;Shimamura, Masako
• 通讯作者: Shimamura, Masako