Cytomegalovirus- and interferon-related effects on human endothelial cells. Cytomegalovirus infection reduces upregulation of HLA class II antigen expression after treatment with interferon-gamma.
ABSTRACT Cultured human umbilical vein endothelial cells (HUVEs) were infected with human cytomegalovirus (HCMV) strain AD169. Up to 50% HUVEs proved to be positive for HCMV early nuclear antigens 24 hours after inoculation with virus. Following infection kinetics of surface expression of HLA class I and II, intercellular adhesion molecule (ICAM-1) and endothelial lymphocyte adhesion molecule (ELAM-1) on HUVEs were investigated by means of flow cytometry. A slight increase in HLA class I expression was observed, whereas expression of HLA class II (DR, DP, DQ) antigens was not induced by infection with HCMV. Furthermore, when compared with uninfected cells treated with interferon-gamma (IFN-gamma), reduced enhancement of HLA-DR expression was conspicuous in HCMV-infected cells treated with IFN-gamma. There is evidence that only a portion of HUVE is affected in its ability to upregulate HLA class II antigens. While expression of ICAM-1 was found to be enhanced between 8 and 20 hours after infection with a maximum at 12 hours after infection, no modulation of ELAM-1 was seen.
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ABSTRACT: The endothelium represents an important therapeutic target for containment of oxidative stress, thrombosis and inflammation involved in a plethora of acute and chronic conditions including cardiovascular and pulmonary diseases and diabetes. However, rapid blood clearance and lack of affinity to the endothelium compromise delivery to target and restrict medical utility of antioxidant enzymes (e.g., catalase) and fibrinolytics. The use of "stealth" PEG-liposomes prolongs circulation, whereas conjugation with antibodies to endothelial determinants permits targeting. Constitutive endothelial cell adhesion molecules (CAM, such as ICAM-1 and PECAM-1, which are stably expressed and functionally involved in oxidative stress and thrombosis) are candidate determinants for targeting of antioxidants and fibrinolytics. CAM antibodies and compounds conjugated with anti-CAM bind to endothelial cells and accumulate in vascularized organs (preferentially, lungs). Pathological stimuli enhance ICAM-1 expression in endothelial cells and facilitate targeting, whereas PECAM-1 expression and targeting are stable. Endothelial cells internalize 100-300 nm diameter conjugates possessing multiple copies of anti-CAM, but not monomolecular antibodies or micron conjugates. This permits size-controlled sub-cellular targeting of antioxidants into the endothelial interior and fibrinolytics to the endothelial surface. Targeting catalase to PECAM-1 or ICAM-1 protects endothelial cells against injury by oxidants in culture and alleviates vascular oxidative stress in lungs in animals. Anti-CAM/catalase conjugates are active for a few hours prior to lysosomal degradation, which can be delayed by auxiliary drugs. Conjugation of fibrinolytics to monovalent anti-ICAM permits targeting and prolonged retention on the endothelial surface. Therefore, CAM targeting of antioxidants and fibrinolytics might help to contain oxidative and thrombotic stresses, with benefits of blocking CAM. Avenues for improvement and translation of this concept into the clinical domain are discussed.Current Pharmaceutical Design 02/2005; 11(18):2383-401. · 3.29 Impact Factor
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ABSTRACT: Cytomegalovirus (CMV) pneumonia is associated with the development of secondary immunosuppression with resultant bacterial and fungal superinfections. Because class II HLA expression within the lung may be important in normal pulmonary cell-mediated immunity, the association of CMV infection of alveolar epithelial cells (AEC) with an absence of HLA class II antigens was tested. Using dual-labeling immunohistochemistry to detect CMV, AEC, endothelial cells, macrophages, and HLA class II antigens, lung tissue from patients whom died with CMV pneumonia was examined. Seventy-five percent of infected cells were AEC. In contrast to adjacent noninfected AEC, which expressed HLA-DR antigens, 91% of infected AEC were negative. There was no difference in this expression pattern between patients with or without AIDS. The absence of HLA class II antigens on infected AEC may account, in part, for the secondary immunosuppression associated with CMV pneumonia.The Journal of Infectious Diseases 02/1995; 171(1):39-44. DOI:10.1093/infdis/171.1.39 · 5.78 Impact Factor
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ABSTRACT: After transplantation, human cytomegalovirus (HCMV) infections can cause vascular damage to both the graft and the host. To study a possible relationship between the degree of vascular injury, clinical symptoms of HCMV infection, and transplant rejection, the appearance and numbers of endothelial cells (ECs) in blood of 54 kidney transplant recipients were investigated in a prospective clinical study. Two types of endothelial cells were identified: cytomegalic ECs (CECs) were detected in patients with moderate or high HCMV antigenemia, and uninfected ECs were observed in patients with and without HCMV infection. The incidence of either CECs, ECs, or the combination of both was associated with HCMV-related clinical symptoms (P<.01). Remarkably, the occurrence of rejection episodes before HCMV infection was an important risk factor for the occurrence of ECs in blood (ECs, CECs, or both) during HCMV infection (P<.001).The Journal of Infectious Diseases 02/2000; 181(2):721-4. DOI:10.1086/315266 · 5.78 Impact Factor