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（由申请方提供）：HIV联合抗病毒治疗（cART）的目标是抑制病毒复制并恢复免疫功能。这是可能的现代cART，但免疫重建（IR）往往是不完全的，显着的免疫异常持续存在，即使在多年的治疗。驱动这些持续性免疫异常的潜在机制可能与全身免疫激活（IA）在治疗患者中未完全正常化的事实有关。慢性IA对淋巴组织的解剖结构具有不利影响，并且是治疗的HIV感染中不完全IR的主要因素。慢性IA与多种炎性细胞因子的表达相关，包括TGF-β，其启动继发性LN和GALT的滤泡旁T细胞区（TZ）中的胶原沉积过程。TZ纤维化的这种累积的渐进过程破坏成纤维细胞网状网络（FRCn），其是形成TZ骨骼解剖结构的中空纤维网。T细胞绝对需要与FRCn接触以进行迁移，形成免疫应答，从FRCn获得生存所需的IL-7。FRCn的丢失与受损的T细胞存活相关，特别是幼稚和中央记忆（CM）表型。这至少部分解释了cART背景下不完全IR和持续免疫异常的机制。我们已经在SIV感染的非人灵长类动物模型中进行了两项初步研究，以使用TGF-β抑制剂吡非尼酮阻止和/或逆转TZ纤维化。我们在初步数据中显示了这种方法的成功，这为我们提出的TGF-β抑制剂在人类HIV感染中的初步研究提供了理论基础，以确定是否有可能恢复FRCn，从而改善免疫功能。我们将在50名接受cART的HIV+患者中进行双盲安慰剂对照研究，使用药物氯沙坦，FDA批准的血管紧张素受体抑制剂（ARB），可在SMAD 2，3的磷酸化水平上抑制TGF-β，动物和人体研究表明，它可逆转肺，肝和肾中现有的纤维化。我们不会使用吡非尼酮，因为它在美国未经FDA批准，并且无法从生产它的公司获得。但是，我们坚信氯沙坦在概念验证试验中是更合适的选择。抗胶原蛋白形成的作用机制与吡非尼酮相同，安全性和耐受性良好，具有长期和既定的安全性记录。重要的是，与吡非尼酮不同，氯沙坦还抑制刺激胶原蛋白产生的基质金属蛋白酶，并具有抗炎特性，在更广泛的背景下可能是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），并降低肿瘤坏死因子（TNF）、IL-6和可溶性粘附分子的水平。我们的假设是用氯沙坦治疗将1）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CD 4 T细胞及其功能;和5）安全且耐受良好。