T lymphocyte-induced glial activation during CNS immune reconstitution disease

CNS 免疫重建疾病期间 T 淋巴细胞诱导的神经胶质活化

基本信息

批准号：
9090147
负责人：
James R Lokensgard
金额：
$ 38万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9090147
关键词：
Address Adoptive Transfer Animals Anti-Retroviral Agents Antigens Area Automobile Driving Back Brain Brain Injuries CD3 Antigens CD4 Positive T Lymphocytes CD80 gene CD8B1 gene Cell Communication Cells Central Nervous System Diseases Central Nervous System Infections Cessation of life Clinical Clinical Research Coculture Techniques Complication Cytotoxic T-Lymphocytes Deterioration Disease Distal Frequencies Funding Grant HIV HIV Infections Health Herpesviridae Host Defense IL2RA gene ITGAM gene Immune Immune system Immunotherapy In Vitro Infection Inflammatory Interferons Interleukin-10 Knockout Mice Knowledge Laboratories Lymphopenia MHC Class I Genes MHC Class II Genes Mediator of activation protein Medicine Microglia Modeling Murine Acquired Immunodeficiency Syndrome Mus Nerve Degeneration Neuraxis Neuroglia Neurologic Neurons Onset of illness Opportunistic Infections PTPRC gene Pathway interactions Patients Peripheral Recombinants Recovery Regulatory T-Lymphocyte Rest Role Severities Signal Transduction Specificity Stroke Syndrome T cell response T memory cell T-Cell Receptor T-Lymphocyte TNFRSF5 gene TNFSF5 gene Testing Time Transforming Growth Factors Transgenic Mice Transplantation Viral Virus Virus Diseases antiretroviral therapy design diphtheria toxin receptor disability fluorescence imaging glial activation immune activation in vivo knockout animal neuroinflammation neurotoxic novel novel therapeutic intervention pathogen reconstitution research study response

项目摘要

DESCRIPTION (provided by applicant): Immune reconstitution inflammatory syndrome (IRIS) has emerged as a major clinical complication in the management of HIV infection following the initiation of combination antiretroviral therapy (cART). IRIS is most commonly seen in patients with severe T cell lymphopenia at the initiation of treatment, often in the presence of an opportunistic infection. cART-induced reversal of lymphopenia restores host defense, but the T- cell repertoire that comes back is often of limited diversity and hyper-responsive to particular antigens due to differential expansion of specific memory T-cells. A wide variety of opportunistic pathogens have been associated with IRIS and heterogeneous clinical manifestations are observed. However, independent of the underlying pathogen or even in the absence of identifiable opportunistic infection, IRIS is characterized by excessive immune activation with elevated frequencies of reconstituting activated T-cells. Immune recovery which specifically attacks the brain is termed central nervous system (CNS)-IRIS and it is particularly challenging due to its clinical severity. Still, the neuroimmunopathogenic mechanisms resulting in CNS-IRIS are poorly understood. Results obtained in our laboratory over the previous funding period of this grant have shown that brain-infiltrating, virus-specific T lymphocytes from the peripheral immune system activate resident microglial cells, including those in widespread areas distal to focal viral infection. Building upon these findings, the central hypothesis to be tested in this competitive renewal application is that replenished yet dysregulated T-lymphocytes drive CNS-immune reconstitution disease (IRD) by providing signals which promote hyper-activation of resident microglia and the overproduction of neurotoxic mediators. In the proposed studies, we will first determine whether T-cell reconstitution of lymphopenic mice harboring herpesvirus brain infection hyper-activates resident microglial cells. This will be achieved through adoptive transfer of CD3(+) T-cells into lymphopenic animals followed by assessment of microglial activation. We will then determine how Foxp3(+) regulatory T-cell (Treg) dysregulation contributes to CNS-IRD. These studies will employ Foxp3-DTR (diphtheria toxin receptor) expressing transgenic mice to determine the effect of depleting Tregs from CD3(+) T-cells prior to adoptive transfer into infected, lymphopenic animals. The final set of experiments will determine mechanisms by which T-cell reconstitution potentiates neurodegeneration. Identification of the precise interactions between T lymphocytes and microglia which drive hyperactive neuroimmune responses is vitally important to the field of HIV medicine. Novel therapeutic approaches (e.g., Treg immunotherapy) which target distinct neuropathogenic pathways are urgently needed. However, the mechanisms to target are still poorly understood because they are difficult to address through clinical studies. In this application, we propose to fill this gap in knowledge by studying experimental CNS-IRD using T-cell repopulation of lymphopenic murine hosts harboring opportunistic viral brain infection.

描述（由申请人提供）：免疫重建炎症综合征（IRIS）已成为启动抗逆转录病毒疗法（CART）后HIV感染管理的主要临床并发症。虹膜通常在患有机会感染的情况下开始治疗时最常见于严重的T细胞淋巴细胞减少症患者。卡车引起的淋巴细胞减少症的逆转恢复了宿主防御，但是由于特定记忆T细胞的差异扩大，返回的T细胞库通常具有有限的多样性和对特定抗原的过度反应。各种各样的机会病原体与虹膜有关，观察到异质的临床表现。然而，与潜在的病原体或甚至没有可识别的机会感染无关，虹膜的特征是过度免疫激活，重建活化的T细胞的频率升高。特异性攻击大脑的免疫恢复称为中枢神经系统（CNS）-IRIS，由于其临床严重程度，它尤其具有挑战性。尽管如此，引起CNS-IRIS的神经免疫发育机制知之甚少。在本赠款的前一期资金期间，我们的实验室获得的结果表明，来自外周免疫系统的脑浸润，病毒特异性T淋巴细胞激活居民的小胶质细胞，包括广泛区域的局灶性病毒感染远处的细胞。在这些发现的基础上，在此竞争性更新应用中要检验的中心假设是补充但失调的T淋巴细胞驱动CNS-免疫重建疾病（IRD），通过提供信号来促进过度激活驻留的小胶质细胞和神经毒性中毒性媒介物的过度生产。在拟议的研究中，我们将首先确定携带疱疹病毒脑感染的淋巴细胞减少小鼠的T细胞重建是否会超过居住的小胶质细胞。这将通过将CD3（+）T细胞传递到淋巴细胞动物中，然后评估小胶质细胞激活来实现这一点。然后，我们将确定FOXP3（+）调节性T细胞（TREG）失调如何有助于CNS-ERD。这些研究将采用表达转基因小鼠的FOXP3-DTR（白喉毒素受体），以确定从CD3（+）T细胞中耗尽的Treg的影响，然后再传递到受感染的，受感染的淋巴细胞动物中。最后一组实验将确定T细胞重建增强神经变性的机制。鉴定T淋巴细胞与小胶质细胞之间的精确相互作用，这些相互作用驱动多动神经免疫反应对HIV医学领域至关重要。迫切需要采用新颖的治疗方法（例如Treg免疫疗法），该方法迫切需要针对不同的神经病途径。但是，目标机制仍然很少了解，因为它们难以通过临床研究来解决。在此应用程序中，我们建议通过研究具有机会性病毒脑感染的淋巴细胞鼠宿主的T细胞重现来填补这一知识的差距。