Mesenchymal stem/stromal cells to enhance cytotoxic T cell immunity during HIV infection

间充质干细胞/基质细胞增强 HIV 感染期间的细胞毒性 T 细胞免疫

基本信息

批准号：
10592965
负责人：
Amir Kol
金额：
$ 31.94万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592965
关键词：
Acquired Immunodeficiency Syndrome Adopted Allogenic Animals Autopsy B-Lymphocytes BLR1 gene Biological Assay Blood CD8-Positive T-Lymphocytes Chronic Clinical Trials Color Complex Confocal Microscopy Cytotoxic T-Lymphocytes Data Development Epigenetic Process Exclusion Flow Cytometry Foundations Functional disorder Genetic Transcription Goals Granzyme HIV HIV Infections HIV/AIDS Helper-Inducer T-Lymphocyte Immune Immune response Immunity Immunohistochemistry In Situ In Vitro Infiltration Infusion procedures Interruption Intestinal Mucosa Intravenous infusion procedures Knowledge Location Lymphoid Follicle Macaca Macaca mulatta Malignant Neoplasms Mesenchymal Microanatomy Mission Modeling Molecular Pathogenesis Patients Peripheral Phenotype Population Process Production Property Public Health Rejuvenation Research Research Project Grants Role SIV Safety Sampling Scientist Site Solid Sorting Stains Stromal Cells T-Cell Proliferation T-Lymphocyte Testing Therapeutic Tissues Translational Research Veterinarians Viral Viral Load result Viral reservoir Virus Virus Diseases Virus Latency Virus Replication antiretroviral therapy cell killing cytokine exhaust exhaustion global health immune cell infiltrate immunoregulation improved innovation lymph nodes molecular marker nonhuman primate novel novel therapeutics peripheral blood pre-clinical programs receptor response single-cell RNA sequencing stem therapeutic candidate therapeutic target trafficking viral rebound

项目摘要

Multipotent stem/stromal cells (MSC) are promising candidate therapeutics for HIV infection, given their potent immunomodulatory properties and wide safety margins. It remains unknown if MSC can reverse CD8 T cell exhaustion and promote trafficking of CD8 T cells into privileged sites during chronic HIV infection. Thus, there is a critical need to determine whether CD8 T cell exhaustion can be therapeutically targeted by MSC. Our long-term goal is to define mechanisms of MSC-induced immune-modulation during chronic viral infections so that improved therapeutic strategies be developed. Our overall objective in this application is to determine if MSC treatment can enhance viral clearance via reversal of exhausted CD8 T cells in chronic SIV-infected macaques. Our central hypothesis is that systemic infusions of allogeneic MSC enhance viral clearance in ART-naïve, and delay viral rebound upon ART interruption in ART-treated SIV-infected macaques, via reversal of CD8 T cell exhaustion and infiltration of privileged sites. The rationale that underlies the proposed research is that CD8 T cell exhaustion and viral sequestration are major mechanisms of HIV viral persistence that may be targeted with MSC treatment. To test our hypothesis we will use the SIV-infected non-human primate model of AIDS. SIV-infected animals will be treated with a combination of ART and/or MSC and samples from peripheral blood, gut tissue, and lymph nodes will be collected during necropsies. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the impact of MSC treatment on exhausted CD8 T cell populations in rhesus macaques chronically infected with SIV. Our working hypothesis is that MSC treatment reverses CD8 T cell exhaustion that is driven by chronic SIV infection. We will sort CD8 T cells from blood, gut tissue, and lymph nodes and perform single-cell RNAseq analysis, multi-color flow cytometry, and ex-vivo stimulation assays. 2) Determine the impact of MSC treatment on CD8 T cell trafficking into lymphoid follicles in rhesus macaques chronically infected with SIV. Our working hypothesis is that MSC treatment in chronic SIV-infected macaques enhances CXCR5+/CD8 T cell trafficking into B-cell follicles. We will determine the micro-anatomical distribution and phenotype of SIV-specific CD8 T cells and viral reservoirs in gut tissue and lymph nodes via in situ MHC-tetramer, and immunohistochemistry staining, and confocal microscopy. The research proposed in the application is innovative because it explores a new therapeutic paradigm of targeting multiple mechanisms of HIV persistence concurrently on multiple mechanistic levels. The proposed research is significant because HIV/AIDS remains a significant global health crisis that is partially driven by viral persistence despite effective antiretroviral therapy and suppression of viral replication. Moreover, as CD8 T cell exhaustion has been implicated in the pathogenesis of multiple other chronic viral diseases and malignancies, findings stemming from this study have the potential to impact broadly and deeply. Findings from this study are directly translatable as MSC are readily available for clinical trials.

鉴于其有效的免疫调节特性和宽阔的安全边缘。 MSC是否可以逆转CD8 T细胞仍然未知在慢性艾滋病毒感染期间，精疲力尽并促进将CD8 T细胞运输到特权部位。那，那里确定CD8 T细胞耗尽是否可以由MSC热靶向是至关重要的。我们的长期目标是定义慢性病毒感染期间MSC诱导的免疫调节机制这种改进的治疗策略将开发出来。我们在此应用程序中的总体目标是确定是否 MSC治疗可以通过慢性SIV感染的反向CD8 T细胞增强病毒清除率猕猴。我们的中心假设是同种异体MSC的全身输注在通过逆转，Art-No-Ne-Ne-Ne-Ne-Ne-Ne-No-Ne-Ne-Ne-Ne-No-Ne-Ne-Ne-Ne-Ne-Ne-Ne-Ne-Ne-Ne-Ne-No-No-Ne-No-No-Ne-No-Ne A Art Rebound Art Art Dient Intrument Intruption Art Intruption中断。 CD8 T细胞耗尽和特权地点的渗透。拟议研究基础的基本原理是CD8 T细胞耗尽和病毒疗法是HIV病毒持久性的主要机制对MSC治疗进行靶向。为了检验我们的假设，我们将使用SIV感染的非人类私人模型艾滋病。 SIV感染的动物将通过艺术和/或MSC的组合以及来自在尸检期间将收集外周血，肠道组织和淋巴结。中心假设将通过追求两个具体目标来测试：1）确定MSC处理对耗尽的CD8 T细胞的影响长期感染SIV的恒河猕猴中的种群。我们的工作假设是MSC治疗逆转由慢性SIV感染驱动的CD8 T细胞耗尽。我们将从血液，肠道中排序CD8 T细胞组织和淋巴结并进行单细胞RNASEQ分析，多色流式细胞仪和前体体刺激测定。 2）确定MSC处理对CD8 T细胞运输淋巴卵泡的影响在长期感染SIV的恒河猕猴中。我们的工作假设是MSC治疗慢性 SIV感染的猕猴增强了CXCR5+/CD8 T细胞运输到B细胞收缩中。我们将确定 SIV特异性CD8 T细胞和肠道组织中的SIV特异性CD8 T细胞和病毒储量的微观动物分布和表型通过原位MHC四聚体和免疫组织化学染色和共聚焦显微镜进行的淋巴结。这应用程序中提出的研究具有创新性，因为它探讨了靶向的新治疗范式艾滋病毒持久性的多种机制在多个机械水平上同时同时。拟议的研究是意义重大，因为艾滋病毒/艾滋病仍然是一场重大的全球健康危机，部分由病毒驱动持久性拼命有效的抗逆转录病毒疗法和病毒复制的抑制。而且，作为CD8 T细胞在多种其他慢性病毒疾病和恶性肿瘤的发病机理中，精疲力尽已被浸渍，这项研究的发现有可能对广泛和深刻的影响。这项研究的发现是可以直接翻译为MSC的临床试验。