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：
8862533
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8862533
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 Knowledge Laboratories Lymphopenia MHC Class I Genes MHC Class II Genes Mediator of activation protein Medicine Microglia Modeling Murine Acquired Immunodeficiency Syndrome Mus Near-infrared optical imaging 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 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）：在开始联合抗逆转录病毒治疗（cART）后，免疫重建炎症综合征（IRIS）已成为治疗 HIV 感染的主要临床并发症。 IRIS 最常见于治疗开始时出现严重 T 细胞淋巴细胞减少症的患者，通常存在机会性感染。 cART 诱导的淋巴细胞减少逆转可恢复宿主防御，但由于特定记忆 T 细胞的差异扩增，恢复的 T 细胞库通常多样性有限，并且对特定抗原过度敏感。多种机会病原体与 IRIS 相关，并且观察到不同的临床表现。然而，独立于潜在的病原体，甚至在没有可识别的机会性感染的情况下，IRIS 的特点是过度的免疫激活和重建激活 T 细胞的频率升高。专门攻击大脑的免疫恢复被称为中枢神经系统 (CNS)-IRIS，由于其临床严重性，它特别具有挑战性。尽管如此，导致 CNS-IRIS 的神经免疫致病机制仍知之甚少。我们实验室在本次资助的上一个资助期间获得的结果表明，来自外周免疫系统的脑浸润性病毒特异性 T 淋巴细胞激活了驻留的小胶质细胞，包括位于局灶性病毒感染远端广泛区域的小胶质细胞。基于这些发现，在这一竞争性更新应用中要测试的中心假设是，补充但失调的 T 淋巴细胞通过提供促进驻留小胶质细胞过度激活和神经毒性介质过量产生的信号来驱动中枢神经系统免疫重建疾病 (IRD) 。在拟议的研究中，我们将首先确定携带疱疹病毒脑部感染的淋巴细胞减少小鼠的 T 细胞重建是否会过度激活驻留的小胶质细胞。这将通过将 CD3(+) T 细胞过继转移到淋巴细胞减少的动物中，然后评估小胶质细胞的活化来实现。然后我们将确定 Foxp3(+) 调节性 T 细胞 (Treg) 失调如何导致 CNS-IRD。这些研究将使用表达Foxp3-DTR（白喉毒素受体）的转基因小鼠来确定在过继转移至感染的淋巴细胞减少动物之前从CD3（+）T细胞中消除Tregs的效果。最后一组实验将确定 T 细胞重建增强神经退行性变的机制。识别驱动过度活跃的神经免疫反应的 T 淋巴细胞和小胶质细胞之间的精确相互作用对于 HIV 医学领域至关重要。迫切需要针对不同神经病理途径的新型治疗方法（例如 Treg 免疫疗法）。然而，由于很难通过临床研究来解决，人们对靶向机制仍然知之甚少。在此应用中，我们建议通过使用携带机会性病毒脑感染的淋巴细胞减少小鼠宿主的 T 细胞再增殖来研究实验性 CNS-IRD，以填补这一知识空白。