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: 8617223
• 负责人: Timothy W Schacker
• 金额: $ 111.73万
• 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/8617223
• 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（申请人提供）：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。现代 cART 可以实现这一点，但免疫重建 (IR) 往往不完整，即使经过多年治疗，显着的免疫异常仍然持续存在。驱动这些持续性免疫异常的潜在机制可能与治疗患者的全身免疫激活（IA）未完全正常化有关。慢性 IA 对淋巴组织的解剖结构有不利影响，并且是治疗 HIV 感染后出现不完全 IR 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-β，其启动次级 LN 和 GALT 的滤泡旁 T 细胞区 (TZ) 中胶原沉积的过程。 TZ 纤维化的这种累积、渐进过程破坏了成纤维细胞网状网​​络 (FRCn)，该网络是形成 TZ 骨骼解剖结构的中空纤维网。 T 细胞绝对需要与 FRCn 接触才能迁移、形成免疫反应、从 FRCn 获得生存所需的 IL-7。 FRCn 的缺失与 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 cART 背景下不完全 IR 和持续免疫异常的机制。我们在 SIV 感染的非人类灵长类动物模型中进行了两项试点研究，以使用 TGF-¿ 抑制剂吡非尼酮来阻止和/或逆转 TZ 纤维化。我们在初步数据中展示了这种方法的成功，这为我们提出的人类 HIV 感染中的 TGF-β 抑制剂初步研究提供了理论依据，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 HIV+ 患者中进行一项双盲安慰剂对照研究，使用药物氯沙坦进行 cART，氯沙坦是 FDA 批准的血管紧张素受体抑制剂 (ARB)，可在 SMAD 2,3 磷酸化水平上抑制 TGF-¿，动物和人类研究表明它可以逆转肺、肝和肾中现有的纤维化。我们不会使用吡非尼酮，因为它未在美国获得 FDA 批准，并且其生产公司无法提供。然而，我们坚信，在概念验证试点试验中，氯沙坦是更合适的选择。对抗胶原蛋白形成的作用机制与吡非尼酮相同，并且安全且耐受性良好，具有长期且已建立的安全记录。重要的是，与吡非尼酮不同，氯沙坦还抑制刺激胶原蛋白生成的基质金属蛋白酶，并具有抗炎特性，这些特性可能在更广泛的背景下发挥作用。它抑制 LPS 诱导的炎症信号（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，氯沙坦治疗将 1) 降低 IA 水平，如 IL-6、TNF、ICAM-1 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) 安全且耐受性良好。