POMC PEPTIDE SYNTHESIS BY NORMAL AND AIDS LEUKOCYTES

正常和艾滋病白细胞合成 POMC 肽

• 批准号: 3241616
• 负责人: DAVID N ORTH
• 金额: $ 12.93万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-02-01 至 1992-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3241616
• 关键词: AIDS; HIV infections; Newcastle disease virus; adrenocorticotropic hormone; aldosterone; antiserum; bacterial antigens; concanavalin A; corticosterone; dexamethasone; gene expression; hormone receptor; hormone regulation /control mechanism; human subject; hydrolase; immunocytochemistry; immunogenetics; immunoregulation; interferons; leukocyte activation /transformation; messenger RNA; molecular pathology; monocyte; nucleic acid probes; peptide chemical synthesis; peptide hormone biosynthesis; proopiomelanocortin; staphylococcal enterotoxin; vasopressins

The lethal defect in acquired immune deficiency syndrome (AIDS) is the profound defect in immune function caused by initial loss of helper T lymphocytes and eventually of all immune competent cells. Little has been published about hypothalamic-pituitary-adrenal (HPA) axis function in AIDS and AIDS-related complex (ARC), but cytomegalovirus adrenalitis, occasionally causing adrenal insufficiency, is surprisingly common. In addition, there is progressive loss of adrenocortical 18-hydroxylase activity in ARC and AIDS, perhaps reflecting loss of a factor separate from ACTH that stimulates aldosterone biosynthesis. With the immune system's first line of defense crippled, the HPA axis assumes an even greater importance in responding to the stress of infection. Furthermore, JE Blalock, EM Smith, WJ Meyer 111 and their coworkers have presented a body of data which indicate that immunocompetent cells produce proopiomelanocortin (POMC) peptides in response to the same agents that induce human leukocyte interferon (hlFN alpha), that POMC production is regulated by the same hormones that regulate anterior pituitary POMC peptide secretion and that these leukocyte-derived POMC peptides may act in an autocrine or paracrine fashion to modulate the immune response and can even directly stimulate adrenocortical steroid biosynthesis in hypophysectomized animals. These findings have potentially fundamentally important implications for regulation of the immune response and interaction of the immune and endocrine systems. However, the only three groups that have attempted to reproduce the findings of Blalock, Smith and Meyer have failed completely to do so. This, the lack of supporting data from other laboratories and questions of proper methodologic rigor raise reservations about this work, although there is little doubt that some immunocompetent cells can synthesize POMC peptides under appropriate conditions. We propose to examine rigorously the essential findings of these investigators, using independent, widely-accepted methods, and extend them by (1) detecting, quantifying and characterizing leukocyte POMC mRNA, (2) determining the concentrations of leukocyte POMC mRNA and peptides in the immune cells and POMC peptides in the medium after stimulation by various agents, (3) determining if there is a leukocyte-derived peptide that specifically stimulates aldosterone biosynthesis, (4) defining which subset(s) of immune cells produce POMC peptides in response to specific stimuli, (5) determining if leukocyte POMC peptide synthesis is impaired in ARC and AIDS and (6) assessing whether leukocyte POMC peptide production is impaired in response to febrile illnesses in AIDS patients. If the findings of Blalock et al are correct, they will be confirmed by the most rigorous examination and will be extended to define possible fundamental defects in immune regulation and immune-endocrine interactions in ARC and AIDS patients.

获得性免疫缺陷综合征（艾滋病）的致命缺陷是 免疫功能的严重缺陷是由最初的免疫功能丧失引起的。 辅助性T淋巴细胞和最终所有免疫活性细胞。 关于下丘脑-垂体-肾上腺的研究很少 (HPA)艾滋病和艾滋病相关综合征（ARC）的轴功能，但 巨细胞病毒肾上腺炎，偶尔引起肾上腺 不足，是令人惊讶的普遍。 此外还有 ARC中肾上腺皮质18-羟化酶活性的进行性丧失 和艾滋病，可能反映了一种与ACTH分离的因子的丢失 刺激醛固酮生物合成。 随着免疫系统的 第一道防线瘫痪，HPA轴假设一个甚至 在应对感染压力方面的重要性更大。 此外，JE Blalock，EM Smith，WJ Meyer 111及其同事 已经提出了一系列数据，表明免疫活性 细胞产生阿黑皮素原（POMC）肽， 诱导人白细胞干扰素（hIFN）的相同试剂 α），POMC的产生是由相同的激素调节的， 调节垂体前叶POMC肽的分泌， 白细胞衍生的POMC肽可以自分泌或 旁分泌方式来调节免疫反应， 直接刺激肾上腺皮质类固醇的生物合成， 切除垂体的动物。 这些发现有可能 对免疫调节的根本重要影响 免疫和内分泌系统的反应和相互作用。 然而，只有三个小组试图复制 布拉洛克、史密斯和迈耶的发现完全没有做到这一点。 是的 这一点，缺乏其他实验室的支持数据， 适当的方法论严谨性问题提出了保留意见， 这项工作，虽然毫无疑问，一些免疫活性， 细胞可以在适当的条件下合成POMC肽。 我们建议严格审查这些研究的主要结果， 调查人员，使用独立的，广泛接受的方法，和 通过（1）检测、量化和表征 白细胞POMC mRNA，（2）测定浓度 免疫细胞和POMC中的白细胞POMC mRNA和肽 各种试剂刺激后培养基中的肽，（3） 确定是否存在白细胞来源的肽， 特异性刺激醛固酮生物合成，（4）定义 免疫细胞的哪一个子集产生POMC肽作为应答 （5）确定白细胞POMC肽是否 在ARC和AIDS中合成受损，以及（6）评估是否 白细胞POMC肽的产生在对以下反应中受损： 艾滋病患者的发热性疾病。 如果Blalock等人的发现 他们是正确的，他们将被最严格的 考试与遗嘱 可以扩展到定义免疫系统中可能存在的基本缺陷 ARC和AIDS中的调节和免疫-内分泌相互作用 患者