Bristow Cynthia L, Ferrando-Martinez Sara, Ruiz-Mateos Ezequiel, Leal Manuel, Winston Ronald
Alpha-1 Biologics, Long Island High Technology Incubator, Stony Brook University, Stony Brook, NY, United States.
Institute for Human Genetics and Biochemistry, Geneva, Switzerland.
Front Cell Dev Biol. 2019 Nov 21;7:278. doi: 10.3389/fcell.2019.00278. eCollection 2019.
Immune cells are, by default, migratory cells that traverse tissue for the purpose of carrying out recognition and recruitment in pathologic inflammation and infection. Members of the LDL receptor family (LDL-RFMs) interact with human leukocyte elastase on the cell surface (HLE-CS) in complex with the abundant blood protein α1proteinase inhibitor (α1PI, α1-antitrypsin, Alpha-1), a process that induces internalization of aggregated functionally-related receptors, including CD4 and the T cell antigen receptor, while simultaneously promoting cellular locomotion. We sought to determine whether augmenting α1PI blood concentration would promote the locomotion of immature T cells through the thymus and generate new CD4 T cells. Two small clinical trials (NCT01370018, NCT01731691, https://clinicaltrials.gov) were conducted in which HIV-1 infected and uninfected individuals were augmented with α1PI and compared with placebo-treated subjects and untreated controls. Blood cell phenotypes were monitored weekly. We found that CD4/CD8 ratio was significantly increased by α1PI augmentation in both uninfected and HIV-1 infected individuals. We found that maturation of CD4CD8 T cells to become immunologically competent CD4 T cells was regulated by α1PI. We propose a strategy targeting HLE-CS for treating secondary immunodeficiency for which there is currently no direct treatment. Treatment to directly elevate T cells in patients with secondary immunodeficiency, including HIV disease, can be provided by alpha-1 antitrypsin augmentation or small molecules that target HLE-CS. Because individuals infected with HIV-1 produce a monoclonal antibody, 3F5, which binds to and inactivates α1PI, a process that prevents α1PI from binding to HLE-CS, thereby blocking locomotion of immature T cells through the thymus to generate CD4 T cells, we further propose that HIV-1 vaccination should include induction of an antibody that binds to and blocks 3F5 activity, thereby preventing AIDS in addition to the current vaccine strategy for preventing HIV-1 infection.
默认情况下，免疫细胞是迁移性细胞，它们穿越组织，以便在病理性炎症和感染中进行识别和募集。低密度脂蛋白受体家族（LDL-RFMs）的成员与细胞表面的人白细胞弹性蛋白酶（HLE-CS）相互作用，该弹性蛋白酶与丰富的血液蛋白α1蛋白酶抑制剂（α1PI、α1抗胰蛋白酶、α1抗胰凝乳蛋白酶）形成复合物，这一过程会诱导包括CD4和T细胞抗原受体在内的聚集的功能相关受体的内化，同时促进细胞运动。我们试图确定提高α1PI血液浓度是否会促进未成熟T细胞穿过胸腺的运动并产生新的CD4 T细胞。我们进行了两项小型临床试验（NCT01370018、NCT01731691，https://clinicaltrials.gov），对感染和未感染HIV-1的个体补充α1PI，并与接受安慰剂治疗的受试者和未治疗的对照组进行比较。每周监测血细胞表型。我们发现，在未感染和感染HIV-1的个体中，补充α1PI均显著提高了CD4/CD8比值。我们发现，α1PI调节CD4CD8 T细胞成熟为具有免疫活性的CD4 T细胞。我们提出了一种针对HLE-CS的策略，用于治疗目前尚无直接治疗方法的继发性免疫缺陷。对于继发性免疫缺陷患者，包括HIV疾病患者，可通过补充α1抗胰蛋白酶或靶向HLE-CS的小分子来直接提高T细胞数量。由于感染HIV-1的个体产生一种单克隆抗体3F5，该抗体与α1PI结合并使其失活，这一过程会阻止α1PI与HLE-CS结合，从而阻断未成熟T细胞穿过胸腺产生CD4 T细胞的运动，我们进一步提出，HIV-1疫苗接种应包括诱导一种能结合并阻断3F5活性的抗体，从而除了目前预防HIV-1感染的疫苗策略外，还能预防艾滋病。
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