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: 2460085
• 负责人: ELIZABETH A RICH
• 金额: $ 28.85万
• 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/2460085
• 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.

肺部经常受到人类免疫缺陷病毒并发症的困扰