Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

逆转组织纤维化以改善艾滋病毒的免疫重建

• 批准号: 8509163
• 负责人: Timothy W Schacker
• 金额: $ 103.63万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-11 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509163
• 关键词: Age; Anatomic structures; Anatomy; Angiotensin Receptor; Animals; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antiviral Therapy; Architecture; Automobile Driving; Bacterial Translocation; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cell Survival; Chronic; Collagen; Cytomegalovirus; Data; Deposition; Disease Progression; Double-Blind Method; Drug Interactions; Drug Kinetics; Drug usage; FDA approved; Fiber; Fibrosis; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV therapy; Hamman-Rich syndrome; Health; Human; IL6 gene; IL7 gene; Immune; Immune response; Immunologics; Infection; Inflammatory; Intercellular adhesion molecule 1; Interleukin-6; Interleukin-7; Intervention; Kidney; Lead; Licensing; Life Expectancy; Liver; Losartan; Lung; Lymphatic; Lymphoid Tissue; Manufacturer Name; Marfan Syndrome; Mediating; Memory; Metalloproteases; Modeling; Pathogenesis; Pathologic; Pathology; Patients; Peptide Hydrolases; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Phosphorylation; Pilot Projects; Pirfenidone; Plasma; Play; Population; Process; Production; Property; Recruitment Activity; Regulatory T-Lymphocyte; Reticular Cell; Role; SIV; Safety; Signal Transduction; Structure; T-Cell Depletion; T-Lymphocyte; Testing; Time; Tissues; Tumor Necrosis Factor-alpha; Vaccines; Viral; Viremia; Virus; base; cytokine; double-blind placebo controlled trial; gastrointestinal epithelium; immune activation; immune function; improved; inhibitor/antagonist; lymph nodes; memory CD4 T lymphocyte; microbial; migration; nonhuman primate; pilot trial; placebo controlled study; prevent; public health relevance; reconstitution; research study; response; skeletal; success

DESCRIPTION (provided by applicant): The goal of combination antiviral therapy (cART) for HIV is to suppress viral replication and restore immune function. This is possible with modern cART however immune reconstitution (IR) is often incomplete and significant immunologic abnormalities persist, even after years of therapy. The underlying mechanisms driving these persistent immune abnormalities are likely related to the fact that systemic immune activation (IA) does not fully normalize in treated patients. Chronic IA has a detrimental effect on the anatomy of lymphoid tissues and is a primary factor in the incomplete IR in treated HIV infection. Chronic IA is associated with expression of multiple inflammatory cytokines, including TGF-¿ that initiates a process of collagen deposition in the parafollicular T cell zone (TZ) of secondary LN and GALT. This cumulative, gradual process of TZ fibrosis destroys the fibroblastic reticular network (FRCn) which is a mesh of hollow fibers that form the skeletal anatomy of the TZ. T cells absolutely require contact with the FRCn for migration, formation of immune responses, gain access to IL-7 from the FRCn that is required for survival. Loss of the FRCn is associated with impaired T cell survival, especially of the naive and central memory (CM) phenotype. This explains, at least in part, the mechanism of incomplete IR and persistent immunologic abnormalities in the setting of cART. We have performed two pilot studies in a non-human primate model of SIV infection to stop and/or reverse TZ fibrosis using the TGF-¿ inhibitor pirfenidone. We show in our preliminary data success with this approach which provides the rationale for our proposed pilot study of a TGF-¿ inhibitor in human HIV infection to determine if there is potential to restore the FRCn and thus improve immune function. We will perform a double-blind placebo controlled study in 50 HIV+ people on cART using the drug losartan, an FDA approved angiotensin receptor inhibitor (ARB) that inhibits TGF-¿ at the level of phosphorylation of SMAD 2,3 and animal and human studies show it reverses existing fibrosis in lung, liver, and kidney. We will not use pirfenidone because it is not FDA approved in the U.S. and is unavailable from the company that makes it. However, we strongly believe losartan is a more suitable choice in a proof of concept pilot trial. The mechanism of action against collagen formation is the same as pirfenidone and it is safe and well tolerated with a long and established safety record. Importantly, and in distinction to pirfenidone, losartan also inhibits matrix metalloproteases that stimulate collagen production and has anti-inflammatory properties that may IA in a broader context. It inhibits LPS-induced inflammatory signaling, an important component of microbial translocation, and decreases levels of tumor necrosis factor (TNF), IL-6, and soluble adhesion molecules. Our hypothesis is that treatment with the losartan will 1) decrease levels of IA as shown by a decrease in IL-6, TNF, ICAM-1; 2) reverse existing fibrosis; 3) restore LN architecture, 4) improve peripheral and lymphatic CD4 T cells and their function; and 5) be safe and well tolerated.

描述（由应用提供）：HIV组合抗病毒疗法（CART）的目的是抑制病毒复制并恢复免疫功能。现代购物车是可能的，但是即使经过多年的治疗，免疫重建（IR）也常常不完整且明显的免疫异常。驱动这些持续的免疫异常的基本机制可能与治疗患者的全身免疫激活（IA）未完全正常化的事实有关。慢性IA对淋巴组织的解剖结构有害作用，是治疗的HIV感染中IR不完全的主要因素。慢性IA与多种炎性细胞因子的表达有关，包括TGF- - 启动胶原蛋白沉积过程中副LN和GALT的层状T细胞区（TZ）。 TZ纤维化的累积分级过程破坏了成纤维细胞网络（FRCN），该网络是形成TZ骨骼解剖结构的空心纤维的网眼。 T细胞绝对需要与FRCN接触以进行迁移，形成免疫反应，从生存所需的FRCN访问IL-7。 FRCN的丧失与T细胞存活受损有关，尤其是幼稚和中央记忆（CM）表型。这至少部分解释了不完整的IR和持续的免疫学异常的机制。我们已经在非人类私有模型的SIV感染模型中进行了两项初步研究，以使用TGF- - 抑制剂Pirfenidone停止和/或反向TZ纤维化。我们通过这种方法在初步数据成功中显示了我们对人类艾滋病毒感染中TGF-抑制剂的试点研究的理由，以确定是否有可能恢复FRCN并改善免疫功能。我们将使用Drug Losartan（FDA批准的血管紧张素受体抑制剂（ARB）在CART上进行双盲安慰剂对照研究，该研究在Smad 2,3的磷酸化水平上抑制TGF- - 抑制TGF- - 动物和人类研究表明，它逆转了Lung，Lung，Liver，Liver，Liver，Liver and five的现有纤维化。我们不会使用Pirfenidone，因为它在美国未获得FDA的批准，并且无法获得制造的公司。但是，我们坚信洛萨坦是概念试验审判证明的更合适的选择。针对胶原蛋白形成的作用机理与吡非酮相同，并且它是安全且重要的，并且与吡芬酮相同，洛萨坦也抑制了刺激胶原蛋白产生并具有抗炎特性的基质金属蛋白酶，并且在更广泛的情况下可能会IA。它抑制LPS诱导的炎症信号传导，微生物易位的重要组成部分，并降低了肿瘤坏死因子（TNF），IL-6和固体粘附分子的水平。我们的假设是，用Losartan的治疗将降低IA水平，如IL-6，TNF，ICAM-1的降低所示； 2）逆转现有的纤维化； 3）恢复LN结构，4）改善外周和淋巴CD4 T细胞及其功能； 5）安全且容忍良好。