Neuroprotective immunity and HIV dementia

神经保护性免疫和艾滋病毒痴呆

基本信息

批准号：
7285772
负责人：
Howard E Gendelman
金额：
$ 36.75万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-04-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7285772
关键词：
4-phenyl-1,2,3,6-tetrahydropyridine AIDS neuropathy Acetates Adjuvant Adoptive Transfer Affect Aluminum Hydroxide Animal Model Animals Anti-Inflammatory Agents Anti-Retroviral Agents Anti-inflammatory Antibodies Antigens Area Astrocytes Autoantigens B-Lymphocytes Biochemical Biological Biological Assay Bone Marrow Brain Brain Injuries CD4 Positive T Lymphocytes CD8B1 gene Cell Communication Cell physiology Cells Cellular Morphology Clinical Condition Cytotoxic T-Lymphocytes Data Dementia Dendritic Cells Developmental Therapeutics Program Disease Dissection Dissociation Dopamine Dose Effector Cell Encephalitis End Point Enzyme-Linked Immunosorbent Assay Exposure to Extracellular Signal Regulated Kinases Fingerprint Genomics Glutamates Grant Granulocyte-Macrophage Colony-Stimulating Factor HIV HIV-1 HLA Antigens Health Human Human Virus Immune Immune system Immunity Immunization Immunocompetent Immunologic Surveillance Immunology Impaired cognition Impairment In Vitro Inflammation Inflammatory Injection of therapeutic agent Interdisciplinary Study Interferon Type II Interferons Interleukin-10 Interleukin-4 Interleukin-5 Interleukin-6 Laboratories Lasers Lead Ligands Link MAPK14 gene Maps Measures Mediating Memory Metabolic Brain Diseases Methods Microglia Microtubule-Associated Proteins Mitogen-Activated Protein Kinases Modeling Molecular Molecular Biology Mononuclear Mus Nerve Degeneration Nerve Growth Factors Nervous system structure Neurodegenerative Disorders Neurons Null Lymphocytes Outcome Parkinson Disease Parkinson&apos s Dementia Pathway interactions Patients Pattern Peripheral Phagocytes Pharmaceutical Preparations Phenotype Physiology Play Population Prevention Proteomics Relative (related person)Research Research Activity Rodent Rodent Model Role Signal Pathway Signal Transduction Spleen Synaptic plasticity System T-Cell Depletion T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Th1 Cells Th2 Cells Therapeutic Time Transforming Growth Factor beta Translating Tumor Necrosis Factor-alpha Vaccines Vasoactive Intestinal Peptide Vesicular stomatitis Indiana virus Viral Viral Encephalitis Virus Virus Diseases Withdrawal Work base brain cell brain tissue cell type concept copolymer 1 cytokine day frontier functional outcomes in vivo lymph nodes macrophage mimetics monocyte neurofilament neuron apoptosis neuroprotection neurotoxic neurotoxicity neurotrophic factor neurotropic reconstitution research study response stress activated protein kinase stress-activated protein kinase 1 virology

项目摘要

DESCRIPTION (provided by applicant): Therapeutic immunization leads to neuroprotection in animal models of HIV-1-associated dementia (HAD) and Parkinson's disease (PD). The mechanism involves modulation of mononuclear phagocyte (MP; macrophages and microglia) inflammation either directly or by regulatory and/or effector T cells. The T-cell-MP interactions protect the brain independent of immune surveillance (anti-retroviral-specific cytotoxic T lymphocytes). The current proposal seeks support to study the mechanisms of how the immune system can be regulated to protect the brain despite a relentless attack by virus and its engagements, independent of anti-retroviral responses. Over the past three of 13 years of this grant cycle significant progress was made in deciphering pathways of how a metabolic encephalopathy is perpetrated through brain MP activation and virus-infection leading to neuronal impairment and cognitive dysfunction. Importantly, this research has evolved and we have been successful in modulating (by glatirimer acetate, GA immunization) a destructive microglia cell to a protective one in murine models of HIV-1 encephalitis. We found that immunization-based neuroprotection involves both innate and adaptive immune systems and that, similar pathways, are operative in animal models of PD making this research broadly applicable in developmental therapeutics for neurodegenerative disorders. Importantly, we now demonstrate that neuroprotection for PD is independent of GA-specific antibody transfers and is T-cell specific. Interestingly, GA elicits innate immune neuroprotection making it potentially useful for patients with significant CD4+ T cell compromise. The work involves an interdisciplinary research approach incorporating immunology, virology, physiology, molecular biology and biochemical approaches used to uncover a microglial profile in health and disease and the means to alter it. Work will proceed from the cell to animal models reflecting HIVE. We posit that effective therapeutic endpoints can be achieved through this work including in immune compromised states and that microglial functional modulation can lead to clinical benefit and new adjunctive therapies in the infected human host.

描述（由申请人提供）：治疗性免疫可在 HIV-1 相关痴呆 (HAD) 和帕金森病 (PD) 动物模型中产生神经保护作用。该机制涉及直接或通过调节和/或效应 T 细胞调节单核吞噬细胞（MP；巨噬细胞和小胶质细胞）炎症。 T 细胞-MP 相互作用可保护大脑，不受免疫监视（抗逆转录病毒特异性细胞毒性 T 淋巴细胞）的影响。目前的提案寻求支持，以研究如何调节免疫系统以保护大脑的机制，尽管病毒及其攻击会不断攻击，而与抗逆转录病毒反应无关。在本资助周期 13 年的过去三年中，在破译代谢性脑病如何通过脑 MP 激活和病毒感染导致神经元损伤和认知功能障碍的途径方面取得了重大进展。重要的是，这项研究已经取得进展，我们已经成功地将 HIV-1 脑炎小鼠模型中的破坏性小胶质细胞（通过醋酸格拉替默、GA 免疫）调节为保护性小胶质细胞。我们发现基于免疫的神经保护涉及先天性和适应性免疫系统，并且相似的途径在帕金森病动物模型中发挥作用，使得这项研究广泛适用于神经退行性疾病的发育治疗。重要的是，我们现在证明 PD 的神经保护独立于 GA 特异性抗体转移，并且是 T 细胞特异性的。有趣的是，GA 能引发先天免疫神经保护作用，使其对 CD4+ T 细胞严重受损的患者可能有用。这项工作涉及一种跨学科研究方法，结合了免疫学、病毒学、生理学、分子生物学和生化方法，用于揭示健康和疾病中的小胶质细胞特征以及改变它的方法。工作将从反映 HIVE 的细胞模型转向动物模型。我们认为，通过这项工作可以实现有效的治疗终点，包括在免疫受损状态下，并且小胶质细胞功能调节可以在受感染的人类宿主中带来临床益处和新的辅助疗法。