Mesenchymal Stem Cell Therapy for Gut Mucosal Recovery in the SIV Model of AIDS

间充质干细胞治疗艾滋病 SIV 模型中肠道粘膜的恢复

• 批准号: 8847248
• 负责人: DORI L. BORJESSON
• 金额: $ 23.45万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847248
• 关键词: Acquired Immunodeficiency Syndrome; Angiogenic Factor; Animals; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Apoptosis; Apoptotic; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Death; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinical Trials; Communicable Diseases; Confocal Microscopy; Data; Development; Disease; Disease Progression; Enterocytes; Enzyme-Linked Immunosorbent Assay; Epithelial; Etiology; Flow Cytometry; Functional disorder; Gap Junctions; Glycoproteins; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immune system; Immunology; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Intestines; Lead; Lymphoid Tissue; Macaca; Macaca mulatta; Measures; Mediating; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Molecular Target; Mucosal Immunity; Mucous Membrane; Natural regeneration; Patients; Primates; Property; Recovery; SIV; Signal Pathway; Signal Transduction; Site; Stem cells; Stromal Cells; T-Lymphocyte; T-Lymphocyte Subsets; Technical Expertise; Testing; Therapeutic; Time; Tissues; Viral; Viral Load result; Virus; Virus Diseases; Western Blotting; adult stem cell; cell injury; gastrointestinal; gastrointestinal epithelium; human STC1 protein; immune activation; improved; injury and repair; innovation; intestinal epithelium; microbial; mucosal site; nonhuman primate; novel therapeutics; peripheral blood; programs; public health relevance; repaired; stem; stem cell biology; stem cell therapy; tissue regeneration; tissue repair

 DESCRIPTION (provided by applicant): The proposed R21 application will investigate the potential of mesenchymal stem/stromal cells (MSC) in enhancing mucosal tissue repair/renewal and immune recovery in HIV-induced chronic inflammatory disease. MSCs secrete immunomodulatory, anti-inflammatory, anti-apoptotic, trophic and angiogenic factors that dampen inflammation and enhance tissue repair and are being actively investigated in several clinical trials. However, the potential of MSCs in tissue renewal during chronic inflammatory diseases of infectious etiology has not been fully explored. HIV disease progression is driven by progressive CD4+ T cell loss and unresolved chronic immune activation. Early pathogenic changes in the gut mucosa in HIV infection may be important in the persistence inflammation and viral reservoirs. Antiretroviral treatment markedly suppresses viral replication but is unable to completely resolve chronic immune activation or eradicate viral reservoirs. An imbalance of inflammatory/anti-inflammatory networks, resulting in inflamed mucosa, may be an important contributor to the persistent immune activation. We propose to utilize simian immunodeficiency virus (SIV) infected non-human primate model of AIDS to investigate potential therapeutic benefits of MSCs and possible mechanisms of action in tissue repair and immune recovery. SIV-infected rhesus macaques are well suited for investigating the therapeutic benefit of MSC transplantation and to elucidate mechanisms of MSC biologic action within the inflamed gut microenvironment. We will test the hypothesis that systemic MSC administration will minimize cell injury and death at mucosal sites in the SIV infected rhesus macaques and facilitate immune recovery. This proposal leverages on our unique strengths in stem cell biology, SIV-infected rhesus macaque model of AIDS, isolation of purified rhesus macaque MSCs and collective technical expertise in MSC cultures, gut mucosal immunology and immune activation. The overall objective of this R21 proposal is to investigate the effects of MSC administration on the gut mucosal repair/renewal and immune recovery and to determine the mechanisms of action in SIV infected rhesus macaques. The study has two specific aims. Aim 1: To determine the effect of MSC therapy on CD4 T cell loss, viral loads and immune activation/inflammation in peripheral blood compartment of SIV infected macaques. Aim 2: To determine the effect of MSC therapy on gut mucosal injury and repair and elucidate the molecular networks mediating its mechanism of action. Changes in T cell subset distribution and cellular activation markers (multicolor flow cytometry, PCR), inflammatory mediators (ELISA), viral loads (real-time PCR), mucosal injury and inflammation (immunohistopathology) and signaling networks for tissue renewal (western blots and qRT-PCR) will be measured. The data will be analyzed to determine the effects of MSC administration in SIV infected animals compared to those not receiving MSC. The proposed study will provide an innovative approach to resolve HIV associated mucosal tissue damage and chronic immune activation through MSC administration in the primate model and will provide rationale for the development of novel therapeutic strategies. The study may elucidate new mechanisms by which MSCs modulate the immune system and promote gut regeneration in chronic inflammatory infections.

 描述（通过应用提供）：拟议的R21应用将研究间充质干/基质细胞（MSC）在增强HIV诱发的慢性炎症性疾病中增强粘膜组织修复/更新和免疫发现的潜力。 MSCS秘密免疫调节，抗炎，抗凋亡，营养和血管生成因子，可在多项临床试验中积极研究，并在几项临床试验中积极研究，并正在积极研究。然而，在感染性病因的慢性炎症性疾病期间，MSC在组织更新中的潜力尚未得到充分探讨。 HIV疾病进展是由进行性CD4+ T细胞丧失和未解决的慢性免疫激活驱动的。 HIV感染中肠粘膜的早期致病性变化在持续性感染和病毒储层中可能很重要。抗逆转录病毒治疗明显抑制病毒复制，但无法完全解决慢性免疫激活或放射性病毒储量。导致粘膜发炎的炎症/抗炎网络的失衡可能是导致持续性免疫激活的重要因素。我们建议利用邻氨酸免疫缺陷病毒（SIV）感染的非人类私人艾滋病模型来研究MSC的潜在治疗益处，以及在组织修复和免疫发现中可能采取的作用机制。 SIV感染的恒河猕猴非常适合研究MSC移植的治疗益处，并阐明发炎的肠道微环境中MSC生物学作用的机制。我们将检验以下假设：系统MSC给药将最大程度地减少SIV感染的恒河猴和维持免疫恢复的细胞损伤和死亡。该提议利用了我们在干细胞生物学，SIV感染的颗粒猕猴模型，纯化的恒河猕猴MSC的隔离以及MSC培养物中的集体技术专业知识，肠粘膜免疫学和免疫激活中的集体技术专业知识。该R21提案的总体目的是研究MSC给药对肠粘膜修复/更新和免疫发现的影响，并确定SIV感染的恒河猴的作用机理。该研究有两个具体的目标。目标1：确定MSC治疗对CD4 T细胞损失的影响，病毒载荷和免疫激活/炎症在SIV感染猕猴的外周血室中的影响。目标2：确定MSC治疗对肠粘膜损伤的影响，并修复并阐明介导其作用机理的分子网络。 T细胞子集分布和细胞激活标记（多色流式细胞术，PCR），炎症介质（ELISA），病毒载荷（实时PCR），粘膜损伤和感染（免疫组织病理学）和信号网络的变化（Western Blots和QRT-PCR）将是测量的。与未接受MSC的动物相比，将对数据进行分析，以确定MSC给药在SIV感染动物中的影响。拟议的研究将提供一种创新的方法来解决通过私人模型中的MSC给药来解决HIV相关的粘膜组织损害和慢性免疫激活，并将为开发新型治疗策略提供理由。该研究可能阐明MSC调节免疫系统并促进慢性炎症感染中的肠道再生的新机制。