NATURAL HISTORY OF LYMPHOCYTIC ALVEOLITIS IN HIV DISEASE

HIV 疾病中淋巴细胞性肺泡炎的自然史

• 批准号: 2231075
• 负责人: ELIZABETH A RICH
• 金额: $ 26.11万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2231075
• 关键词: CD antigens; HIV infections; allergic pneumonitis; autoimmunity; cytotoxic T lymphocyte; human subject; immune system; longitudinal human study; lung alveolus; medical complication; natural killer cells; opportunistic infections; pathologic process; phenotype; polymerase chain reaction; respiratory function; secondary infection; stress proteins; virus antigen

The lung is often beset by complication of human immunodeficiency virus (HIV) infection including opportunistic infections (OI) and noninfectious disorders. How the lung is particularly predisposed to such problems is still not known. Selectivity of organ involvement in HIV-associated disease could be a consequence of local immune dysregulation or in situ expansion of cells due to high viral loads or autoimmune reactions. Lymphocytic alveolitis (LAL) is found in many but not all HIV-infected individuals. The absolute number of alveolar lymphocytes (AL) is increased and there is a predominance of CD8 cells. Natural killer (NK) cells and gamma delta (gamma delta) T cells also may be increased. Although the CD8 cells are cytotoxic to HIV-infected alveolar macrophages (AM), almost nothing is known about the mechanisms of recruitment, activation and regulation of AL, relationship to systemic immune dysregulation, antigenic specificity, or associated consequences on the lung. It is possible, nonetheless, that LAL contributes to the subtle physiologic abnormalities in pulmonary function observed in asymptomatic HIV-infected individuals. Moreover, LAL may represent a condition of asymptomatic HIV-infected subjects fail to suppress expression of early markers of activation on blood T lymphocytes in response to phytohemagglutinin (PHA). Accessory function of these AM for PHA and the superantigen staphylococcal enterotoxin B (SEB) is increased. Dr. Rich found that AM are particularly susceptible to productive infection with HIV in vitro as compared to blood monocytes (MN). Nevertheless, AM from HIV-infected subjects at early stages of HIV disease do not harbor HIV, yet express in response to a variety of stressful insults including viral infections and are remarkably homologous throughout phylogeny. Thus, autoreactivity to HSPs induced by HIV-infected cells could be a basis for autoimmune damage to the lung. Together these findings suggest a two-step hypothesis: HIV-associated LAL may be, in part, a consequence of dysregulation by AM; the loss of the normal control mechanisms by AM, in turn, allows responses to viral or self antigens such as HSPs to proceed unthwarted. The specific aims of this proposal are: (1) To define the natural history of LAL in a longitudinal study of HIV-infected subjects (CD4 strata 300-500/mm3) by examining the phenotype of bronchoalveolar cells (BAC) vs. peripheral blood mononuclear cells (PBMC) and selected functions that could impact on the pathogenesis of LAL; (2) To assess mechanisms and potential consequences of the dysregulation by AM from HIV-infected subjects with LAL; (3) To examine the antigenic specificity of alveolar and blood lymphocytes from HIV-infected subjects with LAL focusing on HIV proteins and HSPs as the target of antigenic reactivity.

肺部常受人类免疫缺陷病毒并发症的困扰 (HIV)感染包括机会性感染（OI）和非感染性感染 紊乱 肺是如何特别容易出现这些问题的， 仍然未知。 HIV相关性免疫缺陷综合征的器官受累选择性 疾病可能是局部免疫失调的结果， 由于高病毒载量或自身免疫反应导致的细胞扩增。 淋巴细胞性肺泡炎（LAL）在许多但不是所有的HIV感染者中发现。 个体 肺泡淋巴细胞（AL）的绝对数量为 增加，并且存在CD 8细胞的优势。 自然杀伤细胞（NK） 细胞和γ δ（γ δ）T细胞也可能增加。 虽然CD 8细胞对HIV感染的肺泡巨噬细胞具有细胞毒性， (AM)，几乎对招募机制一无所知， AL的激活和调节，与全身免疫的关系 失调、抗原特异性或对免疫系统的相关后果。 肺。 尽管如此，LAL可能有助于 在无症状患者中观察到的肺功能生理异常 艾滋病毒感染者。 此外，LAL可以表示 无症状HIV感染者不能抑制早期 血液T淋巴细胞活化标志物 植物血凝素（PHA）。 这些AM对PHA的辅助功能， 超抗原葡萄球菌肠毒素B（SE B）增加。 瑞奇博士 发现AM特别容易受到 与血液单核细胞（MN）相比，体外HIV。 然而，从 处于HIV疾病早期阶段的HIV感染受试者不携带HIV， 然而，在应对各种压力性侮辱时， 感染，并在整个生殖过程中显着同源。 因此，在本发明中， HIV感染细胞诱导的对HSPs的自身反应性可能是HIV感染的基础。 自身免疫性肺损伤 这些发现共同提出了两步假设：HIV相关的LAL 可能部分是AM调节失调的结果; AM的正常控制机制反过来又允许对病毒或 自身抗原，如热休克蛋白进行不受阻碍。 的具体目标 这些建议是：（1）在一个 HIV感染受试者（CD 4分层300-500/mm 3）的纵向研究， 检查支气管肺泡细胞（BAC）与外周血 血液单核细胞（PBMC）和选定的功能，可能会影响 （2）探讨其发病机制和可能的治疗方法， AM对HIV感染受试者的调节异常的后果 （3）检测肺泡和血液抗原的特异性 来自具有侧重于HIV蛋白的LAL的HIV感染受试者的淋巴细胞 和热休克蛋白作为抗原反应性的目标。