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1.
Inhibition of endothelial receptor expression and of T-cell ligand activity by mycophenolate mofetil 总被引:8,自引:0,他引:8
Roman A Blaheta Kerstin Leckel Bianca Wittig Dietmar Zenker Elsie Oppermann Sebastian Harder Martin Scholz Stephan Weber Horst Schuldes Albrecht Encke Bernd H Markus 《Transplant immunology》1998,6(4):251-259
The novel immunosuppressive drug mycophenolate mofetil (CellCept, MMF) blocks DNA-synthesis by the inhibition of the enzyme inosine monophosphate dehydrogenase (IMDH). IMDH is also involved in the synthesis of adhesion receptors which are known to play an important role in the regulation of cell-cell contacts. Therefore, application of MMF might lead to a reduction of cellular infiltrates in the course of transplant rejection. To evaluate the therapeutic value of MMF, we investigated to what extent MMF blocks T-lymphocyte infiltration in vitro with regard to (a) adhesion to endothelial cells, (b) horizontal migration along these cells and (c) penetration through the endothelial cells. The results demonstrated a strong inhibition of both CD4+ and CD8+ T-cell adhesion and penetration by MMF. The ID50 value for CD4+ T-cell adhesion was calculated to be 0.03 microM and the ID50 value for CD4+ T-cell penetration 1.21 microM. MMF did not significantly influence the horizontal migration of T-lymphocytes along the human vascular endothelial cell (HUVEC) borders. FACS-analysis revealed a diminished E-selectin and P-selectin expression on endothelial cell membranes in the presence of MMF. Although MMF did not interfere with the synthesis of T-cell adhesion ligands, the binding activity of lymphocytic leucocyte function associated antigen 1 (LFA-1), very late antigen 4 (VLA-4) and PSGL-1 (P-selectin glycoprotein ligand 1) to immobilized intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P-selectin was impaired. Moreover, MMF prevented VLA-4 and PSGL-1 receptor accumulation on the membranes of T-cell pseudopodia. It can be concluded that MMF possesses potent infiltration blocking properties. MMF evoked down-regulation of specific endothelial membrane molecules and the loss of protein localization in the lymphocyte protrusions might be predominantly responsible for the observed blockade of cell adhesion and penetration. 相似文献
2.
3.
Hypoxia and reoxygenation do not upregulate adhesion molecules and natural killer cell adhesion on human endothelial cells in vitro 总被引:2,自引:0,他引:2
Christine F. Maurus Drthe Schmidt Mrten K. J. Schneider Marko I. Turina Jrg D. Seebach Gregor Zünd 《European journal of cardio-thoracic surgery》2003,23(6):976-983
Objectives: Ischemia/reperfusion injury is characterized by endothelial cell activation leading to increased expression of adhesion molecules such as inter-cellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, endothelial- and platelet-selectin (E- and P-selectin), and to the subsequent recruitment of leukocytes. The aim of the present study was to investigate the respective effects of a proinflammatory cytokine (tumor necrosis factor alpha , TNF-), hypoxia and/or reoxygenation on adhesion molecule expression and natural killer (NK) cell adhesion in an in vitro model of I/R. Methods: Human aortic endothelial cells (HAEC) were stimulated in vitro for 8h with TNF- (1000 U/ml) and exposed to hypoxia (1% O2), reoxygenation (21% O2) or different combinations thereof. Cell surface expression of ICAM-1, VCAM-1 and E-/P-selectin on HAEC was analyzed by flow cytometry, and culture supernatants were tested for soluble adhesion molecules by ELISA. Rolling adhesion of NK cells on HAEC was determined using a rotating assay. Results: Untreated HAEC constitutively expressed ICAM-1 on their surface but neither expressed E-/P-selectin, VCAM-1, nor shedded soluble adhesion molecules. Exposure of HAEC to hypoxia or hypoxia and reoxygenation did not upregulate cell surface expression or shedding of adhesion molecules. In contrast, TNF- significantly upregulated cell surface expression of ICAM-1, VCAM-1, and E-/P-selectin and led to the shedding of ICAM-1 and E-selectin. Combined treatment of HAEC with TNF-, hypoxia and reoxygenation reduced E-/P-selectin surface expression and enhanced E-selectin shedding, but did not further influence ICAM-1 and VCAM-1. Soluble VCAM-1 was not detected. NK cell adhesion on HAEC increased 4-fold after TNF- stimulation, but was not affected by hypoxia or hypoxia and reoxygenation. Conclusions: Both the expression of endothelial adhesion molecules and rolling NK cell adhesion was upregulated by TNF- but not by hypoxia alone or hypoxia followed by reoxygenation supporting the view that anti-inflammatory treatment may reduce ischemia/reperfusion injury. 相似文献
4.
目的探讨黏附分子ICAM-1、P-selectin、E-selectin、L-selectin、PECAM-1和VCAM-1在肝脏移植中的表达及意义。方法用免疫组织化学方法和原位杂交法,检测大鼠肝脏移植后不同时间(1、3、5、7d)、不同模型中ICAM-1、P-selectin、L-selectin、E-selectin蛋白、VCAM-1 mRNA、PECAM-1 mRNA的表达情况。结果肝急性排斥组与自发耐受组相比,黏附分子ICAM-1、VCAM-1、PECAM-1、E-selectin表达高;子代组与肝急性排斥组各指标表达类似,而ICAM-1的表达高于肝急性排斥组;半肝组与自发耐受组各指标表达类似,但ICAM-1、VCAM-1表达水平较自发耐受组高。P-selectin、L-selectin表达变化不明显。而正常大鼠肝脏未见黏附分子的表达。结论肝排斥反应可能与黏附分子ICAM-1、VCAM-1、PECAM-1、E-selectin的高表达有关。 相似文献
5.
Fukatsu K Zarzaur BL Johnson CD Lundberg AH Hanna MK Wilcox HG Kudsk KA 《The Journal of surgical research》2001,97(1):41-48
BACKGROUND: Total parenteral nutrition (IV-TPN) increases neutrophil accumulation in the small intestine, expression of intestinal ICAM-1 and P-selectin, and upregulates E-selectin expression in the lung. Endothelial activation induced by lack of enteral nutrition may change the response to injury or infection. This study investigated whether nutrition influenced the expression of the adhesion molecule, E-selectin and ICAM-1, following endotoxin challenge. MATERIALS AND METHODS: Forty-three mice were injected with saline, 2, 20, 200, 2000, or 10000 microg/kg lipopolysaccharide (LPS) intraperitoneally. E-selectin expression in the lung, small intestine, and heart was quantified at 3 h after challenge, while ICAM-1 was measured at 5 h, using the dual-radiolabeled monoclonal antibody technique. Next, 80 mice were fed chow, intragastric (IG)-TPN, or IV-TPN for 5 days, and then received intraperitoneal 2 or 200 microg/kg LPS. E-selectin and ICAM-1 expression in organs was measured at 3 and 5 h after endotoxin, respectively. RESULTS: E-selectin expression in organs increased LPS dose dependently. ICAM-1 levels reached early peaks in the lung and in the intestine. Also, IV-TPN significantly increased E-selectin expression in the small intestine and tended to increase pulmonary E-selectin, when compared to chow or IG-TPN animals. There were no significant differences in E-selectin expression among three diet groups after 200 microg/kg LPS challenge. No differences in ICAM-1 expression were observed in any organ among the three groups after 2 or 200 microg/kg LPS injection. CONCLUSIONS: E-selectin rather than ICAM-1, because of the expression pattern after various dosages of LPS challenge, may be a determining factor for the degree of LPS-induced inflammation at the early phase. Lack of enteral nutrition may increase inflammatory response through enhanced gut E-selectin levels after a small dose of LPS. 相似文献
6.
BACKGROUND: Intercellular adhesion molecule (ICAM-1) is important in leukocyte adhesion-dependent events and some data suggest that ICAM-1 provides T cell costimulation. We anlayzed the role of the ICAM-1 and leukocyte function associated antigen-1 (LFA-1) interaction in human T cell alloreactivity in vitro. METHODS: Allo-antigen-induced T cell proliferation and cytotoxic T lymphocyte lytic activity were assessed by mixed lymphocyte reaction assay and 51 Chromium release assay, respectively. Immunostaining and flow cytometry were used to assess the expression of receptors on activated T cells. RESULTS: Alloantigen-induced T cell proliferation and cytotoxic T lymphocyte activity were markedly inhibited by antibodies to ICAM-1 and LFA-1. These antibodies had to be present at the time of initial T cell receptor/antigen engagement to inhibit proliferation. Neither IL-2 nor IL-4 were involved in the observed inhibition by antibodies. Inhibition was not associated with altered cell surface expression of receptors such as CD3, CD4, ICAM-1, LFA-1, CD25, and HLA-DR however, these antibodies did impede the ability of generation of functionally active T cells. Interestingly, these antibodies inhibited soluble, but not immobilized OKT3-induced proliferation of peripheral blood leukocytes. Antibody-mediated inhibition of proliferation failed to impair the ability of T cells to subsequently proliferate in response to stimulation by the original or third party alloantigen or mobilize [Ca++]i in response to CD3 or LFA-1 receptor ligation. CONCLUSIONS: These data demonstrate that blockade of ICAM-1/LFA-1 binding at the time of allorecognition potently blocks initial T cell effector functions that could be due to lack of effective T cell/APC engagement. 相似文献
7.
George Asimakopoulos FRCS Kenneth M Taylor FRCS 《The Annals of thoracic surgery》1998,66(6):2135-2144
During the inflammatory response, triggered by cardiopulmonary bypass, interaction between activated leukocytes, platelets, and endothelial cells is mediated through the expression of three main groups of adhesion molecules: the selectins, the integrins, and the immunoglobulin superfamily. The selectins, which mediate the initial rolling of the leukocyte on the endothelium, are divided in three subgroups: L-selectin is expressed on all three leukocyte types, P-selectin is expressed on platelets and endothelial cells, and E-selectin is only expressed on endothelial cells. Integrins can be found on most cell types, consist of an and a β subunit and mediate firm adhesion of the leukocyte and migration into the tissues. They are classified into subgroups according to the type of their β subunit. Immunoglobulins such as ICAM-1 and VCAM-1 are expressed mainly on endothelium and act as ligands for certain integrins. This review article summarizes the existing, and rapidly expanding, literature concerning the effects of cardiopulmonary bypass on the expression of leukocyte and endothelial adhesion molecules. Deeper understanding of the behavior and the role of adhesion molecules during cardiopulmonary bypass may facilitate effective intervention in the inflammatory response process and suppression of its adverse effects. 相似文献
8.
Membrane stabilization in harvested vein graft storage: effects on adhesion molecule expression and nitric oxide synthesis. 总被引:3,自引:0,他引:3
K M Vural M C Oz H Liao H F Batirel D J Pinsky 《European journal of cardio-thoracic surgery》1999,16(2):150-155
OBJECTIVE: Expression of cellular adhesion molecules in human saphenous vein grafts may occur even during harvesting and storage, before the grafts have been implanted as bypass conduits. This may play a role in graft adaptation to arterial flow conditions, which may play an important role in late graft patency. In this study, ketotifen, a mast cell membrane stabilizing agent was studied for its effects on reducing endothelial reactivity during storage of harvested vein graft segments. METHODS: Human saphenous vein grafts, obtained from seven patients and then divided into two equal parts of control and study specimens, were stored in either heparinized blood (Group A) or heparinized blood containing 100 microg/ml ketotifen (Group B) for 1 h at room temperature. Specimens were analyzed by Western blotting to quantify ICAM-1, E-selectin, P-selectin, VCAM-1, and inducible nitric oxide synthase (NOS-2) expression, as well as tissue cGMP levels in response to topical application of an endothelium-independent vasodilator. RESULTS: ICAM-1, E-selectin and P-selectin expression did not differ between the groups. However, VCAM-1 expression was significantly lower in Group B (460 +/- 29 vs. 289 +/- 50, P = 0.01). NOS-2 expression (488 +/- 64 vs. 577 +/- 38, P = 0.02) and tissue cGMP levels (2.2 +/- 0.6 pmol/ml vs. 5.7 +/- 1.7 pmol/ml, P = 0.01) in response to nitroglycerin (24 +/- 10% vs. 11 +/- 5%, P = 0.02) were higher in Group B. CONCLUSIONS: Of all of the adhesion receptors studied, only VCAM-1 expression was reduced by a mast cell membrane-stabilizing agent, perhaps because of activation of the venous endothelium during harvest prior to ketotifen exposure. However, ketotifen also augmented NOS-2 expression, increased tissue cGMP levels in response to nitroglycerin. These actions may improve vascular homeostasis in the venous graft, suggesting the possibility that this strategy may improve long-term graft patency. 相似文献
9.
Chello M Mastroroberto P Frati G Patti G D'Ambrosio A Di Sciascio G Covino E 《The Annals of thoracic surgery》2003,76(2):453-8; discussion 458
BACKGROUND: Mechanical trauma occurring during saphenous vein graft harvesting plays a major role in graft failure after coronary bypass surgery. There is increasing evidence that neutrophil-endothelial interaction is involved in the pathogenesis of early graft occlusion. This study evaluates the effect of pressure distension on the expression of endothelial adhesion molecules in human saphenous vein. METHODS: Segments of saphenous vein graft (SVG) were collected from 20 patients undergoing coronary bypass surgery. We evaluated the expression of intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), and P-selectin on SVG endothelium under basal conditions and after pressure distension at 300 mm Hg. In the same experimental setting we also evaluated adhesion of both unstimulated and activated neutrophils to the endothelium of SVG. RESULTS: Control endothelial cells exhibited only a weak staining for intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), and P-selectin, whereas the levels of adhesion molecules increased significantly in the distended veins. Similarly, significantly greater adhesion of both unstimulated and activated neutrophils was observed in distended veins compared with control veins. CONCLUSIONS: Pressure distension of SVG before coronary bypass surgery induces upregulation of endothelial adhesion molecules, with subsequent increase in neutrophil adhesion to the endothelium. Neutrophil adhesion to endothelial cells may contribute to early failure of SVG. 相似文献
10.
Tissue-specific induction of E-selectin in glomeruli is augmented following diabetes mellitus 总被引:6,自引:0,他引:6
We recently demonstrated that induction of adhesion molecules is tissue, cell type, and blood vessel size specific. We examined here whether the glomeruli, a peculiar vascular system, express adhesion molecules in a specific manner in the murine kidney. In addition, since serum levels of soluble adhesion molecules have been reported to be elevated in diabetic patients, we examined the influence of diabetes mellitus on the induction of adhesion molecules in the kidney. Analysis of E-selectin mRNA expression by in situ hybridization indicated that it was selectively induced in glomeruli by intravenous administration of interleukin-1beta, while ICAM-1 mRNA expression was seen diffusely in endothelium lining the small arteries and capillaries or in glomeruli, and VCAM-1 mRNA expression was most prominent in endothelial cells of larger blood vessels. Induction of E-selectin mRNA expression in glomeruli by proinflammatory stimuli was augmented in streptozotocin-induced diabetic mice as compared with control mice, while ICAM-1 or VCAM-1 mRNA induction was only slightly influenced. Furthermore, immunohistochemical analysis showed that selective expression of E-selectin in glomeruli was augmented predominantly in epithelial cells, depending on the duration of diabetes mellitus, in KK-Ay mice. These findings suggest that glomerulus-specific expression of E-selectin is related to the development of diabetic nephropathy. 相似文献
11.
目的 探讨过氧化物酶体增殖物激活受体-γ(PPAR-γ)激动剂罗格列酮(ROSI)对大鼠急性胰腺炎肺损伤(APALI)黏附分子的作用及其机制.方法 雄性Wistar大鼠54只,随机分为假手术组(SO组)、急性胰腺炎组(SAP组)和罗格列酮预处理组(ROSI组).胆胰管逆行注射5%牛磺胆酸钠制备急性胰腺炎模型.ROSI组造模前30 min经股静脉注射10%二甲基亚砜(DMSO)溶解的罗格列酮(6 mg/kg);SO组、SAP组则注射等量10%DMSO.术后3 h、6 h、12 h分批剖杀大鼠,每个时间点6只.检测血清淀粉酶(AMY)、肺组织髓过氧化物酶(MPO)、肺湿干比(W/D),取肺组织行病理学检查;逆转录聚合酶链反应(RT-PCR)检测肺组织细胞间黏附分子-1(ICAM-1)、P-选择素和E_选择素mRNA表达水平.结果 SAP组各时间点AMY、MPO、W/D和肺组织病理评分均较S0组升高(P<0.05);ROSI组上述指标较SAP组下降,AMY、MPO、W/D和病理评分在6 h、12 h差异有统计学意义(P<0.05).SAP组ICAM-1、P-选择素和E-选择素mRNA表达在12 h达高峰,均较SO组12 h升高(P<0.05),ROSI组上述指标mRNA表达在12 h点均较SAP组下降(P<0.05).结论 罗格列酮通过抑制肺组织IcAM-1、P-选择素和E-选择素的表达,减轻急性胰腺炎肺损伤程度. 相似文献
12.
目的 探讨过氧化物酶体增殖物激活受体-γ(PPAR-γ)激动剂罗格列酮(ROSI)对大鼠急性胰腺炎肺损伤(APALI)黏附分子的作用及其机制.方法 雄性Wistar大鼠54只,随机分为假手术组(SO组)、急性胰腺炎组(SAP组)和罗格列酮预处理组(ROSI组).胆胰管逆行注射5%牛磺胆酸钠制备急性胰腺炎模型.ROSI组造模前30 min经股静脉注射10%二甲基亚砜(DMSO)溶解的罗格列酮(6 mg/kg);SO组、SAP组则注射等量10%DMSO.术后3 h、6 h、12 h分批剖杀大鼠,每个时间点6只.检测血清淀粉酶(AMY)、肺组织髓过氧化物酶(MPO)、肺湿干比(W/D),取肺组织行病理学检查;逆转录聚合酶链反应(RT-PCR)检测肺组织细胞间黏附分子-1(ICAM-1)、P-选择素和E_选择素mRNA表达水平.结果 SAP组各时间点AMY、MPO、W/D和肺组织病理评分均较S0组升高(P<0.05);ROSI组上述指标较SAP组下降,AMY、MPO、W/D和病理评分在6 h、12 h差异有统计学意义(P<0.05).SAP组ICAM-1、P-选择素和E-选择素mRNA表达在12 h达高峰,均较SO组12 h升高(P<0.05),ROSI组上述指标mRNA表达在12 h点均较SAP组下降(P<0.05).结论 罗格列酮通过抑制肺组织IcAM-1、P-选择素和E-选择素的表达,减轻急性胰腺炎肺损伤程度. 相似文献
13.
目的 探讨过氧化物酶体增殖物激活受体-γ(PPAR-γ)激动剂罗格列酮(ROSI)对大鼠急性胰腺炎肺损伤(APALI)黏附分子的作用及其机制.方法 雄性Wistar大鼠54只,随机分为假手术组(SO组)、急性胰腺炎组(SAP组)和罗格列酮预处理组(ROSI组).胆胰管逆行注射5%牛磺胆酸钠制备急性胰腺炎模型.ROSI组造模前30 min经股静脉注射10%二甲基亚砜(DMSO)溶解的罗格列酮(6 mg/kg);SO组、SAP组则注射等量10%DMSO.术后3 h、6 h、12 h分批剖杀大鼠,每个时间点6只.检测血清淀粉酶(AMY)、肺组织髓过氧化物酶(MPO)、肺湿干比(W/D),取肺组织行病理学检查;逆转录聚合酶链反应(RT-PCR)检测肺组织细胞间黏附分子-1(ICAM-1)、P-选择素和E_选择素mRNA表达水平.结果 SAP组各时间点AMY、MPO、W/D和肺组织病理评分均较S0组升高(P<0.05);ROSI组上述指标较SAP组下降,AMY、MPO、W/D和病理评分在6 h、12 h差异有统计学意义(P<0.05).SAP组ICAM-1、P-选择素和E-选择素mRNA表达在12 h达高峰,均较SO组12 h升高(P<0.05),ROSI组上述指标mRNA表达在12 h点均较SAP组下降(P<0.05).结论 罗格列酮通过抑制肺组织IcAM-1、P-选择素和E-选择素的表达,减轻急性胰腺炎肺损伤程度. 相似文献
14.
de Rossi LW Horn NA Weingartz E Buhre W Rossaint R 《Acta anaesthesiologica Scandinavica》2003,47(5):559-563
BACKGROUND: Recruitment of monocytes to inflamed tissue is a crucial step in the acute inflammatory reaction. Adherence of monocytes to endothelial cells followed by transmigration depends on monocyte surface adhesion molecules, inflammatory cytokines and chemoattractant chemokines. In the present study, we determined the effect of isoflurane on monocyte adhesion receptor expression in vitro. METHODS: Citrated whole blood was incubated for 60 min with either 0.5 or 1 MAC isoflurane. In unstimulated blood samples and after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP) monocyte cell-surface expression of the selectins PSGL-1 and L-selectin, and the beta2-integrins CD11a and CD11b were evaluated by flow cytometry. RESULTS: Isoflurane reduced significantly the expression of PSGL-1 on unstimulated monocytes, whereas the remaining selectins and beta2-integrins were not affected. At both concentrations, the FMLP-induced removal of PSGL-1 from the monocyte surface was increased. Furthermore, at 1 MAC isoflurane the FMLP-induced increase in CD11a expression was significantly inhibited. The surface expression of L-selectin and CD11b was not affected following exposure to isoflurane. CONCLUSION: Isoflurane increases the removal of the selectin PSGL-1 from the monocyte surface. Since PSGL-1 is important during the initial step of monocyte adhesion to endothelial P-selectin, the decrease in monocyte surface PSGL-1 may have profound effects on monocyte-endothelial interactions. Furthermore, the effects of isoflurane on monocyte adhesion molecule expression are different from those reported for neutrophils. 相似文献
15.
目的 探讨凋亡及凋亡相关因子Fas/FasL、Bcl-2/Bax,粘附分子ICAM-1、P-selectin、E-selectin、L-Selectin、PECAM-1和VCAM-1在心脏移植中的表达及意义。方法 用免疫组织化学方法和原位杂交法,检测大鼠心脏移植后不同时间(1、3、5、7d)、Fas/FasL、ICAM-1、P-selectin、L-selectin、E-selectin蛋白、Bcl-2/Bax、VCAM-1、PECAM-1 mRNA的表达情况。结果 随着移植后天数的增加,细胞凋亡增多,Fas/FasL、Bax表达增加,粘附分子ICAM-1、VCAM-1、PECAM-1表达也增加,Selectin表达较少。正常大鼠肝脏未见细胞凋亡及粘附分子的表达。结论 细胞凋亡和粘附分子ICAM-1、VCAM-1、PECAM-1表达增加可能与心脏移植后急性排斥反应有关,而Fas/FasL、Bax可能促进了凋亡的发生。 相似文献
16.
B. Mayer H. Spatz I. Funke J. P. Johnson F. W. Schildberg 《Langenbeck's archives of surgery / Deutsche Gesellschaft fur Chirurgie》1998,383(1):81-86
Background and aims: Angiogenesis and the molecular phenotype of the tumor vasculature determine tumor growth and metastasis. Patients/Methods: In a series of 58 gastric cancer patients, vascular density and the antigenic profile of endothelial cells in normal, inflamed
and malignant gastric tissues were compared using immunohistochemistry. Results: In both benign gastric mucosa and primary gastric cancer vascular density was inflammation-independent. However, increased
vascularity in primary tumors was positively associated with a high tumor cell density suggesting tumor-induced angiogenesis
(P=0.00001). P-selectin was expressed in most of the gastric mucosa samples on a small fraction of vessels and increased in
the presence of moderate to strong leukocyte infiltrate. VCAM-1 positive mucosal vessels were rare and showed no association
with inflammation. E-selectin and the EN 7/44 antigen defining budding vessels were absent on normal and inflamed endothelium.
In contrast, in primary gastric cancer de novo expression of both E-selectin and the EN 7/44 antigen was observed. E-selectin
positive vessels were preferentially found in vascular-rich tumor areas (P=0.0043) independently of leukocyte infiltration. Upregulation of VCAM-1 on tumor-associated endothelium was closely related
to inflammation (P=0.019), while P-selectin expression resembled that in benign mucosa. Conclusions: Differentially expressed vascular molecules may influence the functional characteristics of extravasating leukocytes and
represent new targets in anti-gastric cancer therapy.
Received: 30 December 1997 相似文献
17.
Knight DA Briggs BR Bennett CF Harindranath N Waldman WJ Sedmak DD 《Transplantation》2000,69(3):417-426
BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is strongly induced under inflammatory conditions associated with allograft rejection, thereby promoting leukocyte recruitment and activation at the site of inflammation. Enhancement of ICAM-1 expression can also be the result of viral infection, in particular human cytomegalovirus (CMV), a frequent source of complications in the transplant recipient. In vitro studies have shown that CMV infection of endothelial cells (EC) results in the direct enhancement of ICAM-1 expression and consequent leukocyte adhesion/activation suggesting mechanisms by which CMV exacerbates graft vascular disease. Although treatment of EC with ICAM-1-specific antisense oligonucleotides has been shown to attenuate ICAM-1 induction under simulated inflammatory conditions (i.e., TNF-alpha), no studies have addressed their effectiveness on virally-induced ICAM-1 expression. RESULTS: In the current investigation, we show that the progressive increase in endothelial ICAM-1 protein expression that follows inoculation with CMV correlates with a progressive accumulation of ICAM-1 mRNA. Furthermore, we demonstrate that treatment of EC with a partially 2'-O-methoxyethyl modified ICAM-1-specific antisense oligonucleotide before viral inoculation significantly reduces CMV-associated induction of ICAM-1 protein and mRNA expression. Finally, we show that antisense-mediated attenuation in ICAM-1 expression results in a significant reduction of T lymphocyte adhesion to CMV-infected EC monolayers, an interaction that has been implicated in allogeneic T lymphocyte activation, in viral transmission to transiently adherent leukocytes and subsequent hematogenous dissemination. CONCLUSIONS: These findings demonstrate for the first time that antisense oligonucleotides can effectively reverse virally-induced host cellular protein expression, specifically ICAM-1, as well as consequent T lymphocytes adhesion, thus broadening the potential clinical utility of antisense oligonucleotides. 相似文献
18.
Peptides derived from ICAM-1 and LFA-1 modulate T cell adhesion and immune function in a mixed lymphocyte culture. 总被引:7,自引:0,他引:7
S A Tibbetts C Chirathaworn M Nakashima D S Jois T J Siahaan M A Chan S H Benedict 《Transplantation》1999,68(5):685-692
BACKGROUND: The counter receptors intercellular adhesion molecule (ICAM)-1 and lymphocyte function-associated antigen (LFA)-1 are lymphocyte cell surface adhesion proteins the interaction of which can provide signals for T cell activation. This binding event is important in T cell function, migration, and general immune system regulation. The ability to inhibit this interaction with monoclonal antibodies has proved to be therapeutically useful for several allograft rejection and autoimmune disease models. METHODS: Short peptides representing counter-receptor contact domains of LFA-1 and ICAM-1 were examined for their ability to inhibit T cell adhesion and T cell function. RESULTS: Peptides encompassing amino acids Q1-C21 and D26-K50 of ICAM-1, I237-I261 and G441-G466 of the LFA-1 alpha-subunit, and D134-Q159 of the LFA-1 beta-subunit inhibited LFA-1/ICAM-1-dependent adhesion in a phorbol-12,13-dibutyrate-induced model of tonsil T cell homotypic adhesion. This inhibition was specific to the peptide sequence and occurred without stimulation of T cell proliferation. The peptides also were effective in preventing T cell function using a one-way mixed lymphocyte reaction model for bone marrow transplantation. CONCLUSIONS: Our data suggest that these peptides or their derivatives may be useful as therapeutic modulators of LFA-1/ICAM-1 interaction during organ transplants. 相似文献
19.
目的:了解肠缺血-再灌流过程中不同脏器 ICAM-1表达的时间、空间规律。方法:用 RT-PCR 和免疫组化的方法检测肠缺血-再灌流大鼠肠、肝和肺组织中 ICAM-1mRNA 和蛋白表达的变化。结果:肠组织中的ICAM-1 mRNA 和蛋白在肠缺血期及再灌流1h 表达增加,肝脏和肺脏毛细血管内皮上的 ICAM-1表达增加在再灌流后2h 和6h,晚于肠组织,并且与组织中性白细胞的聚集增加一致。结论:肠缺血-再灌流大鼠不同组织的ICAM-1表达的变化呈现序贯性。 相似文献
20.
Dou L Cerini C Brunet P Guilianelli C Moal V Grau G De Smet R Vanholder R Sampol J Berland Y 《Kidney international》2002,62(6):1999-2009
BACKGROUND: Infectious diseases are among the most morbid events in uremia. The uremic toxin p-cresol may play a role in the immunodeficiency of uremia by depressing phagocyte functional capacity. Leukocyte adhesion to endothelium, a key event in the immune response, is mediated by endothelial adhesion molecules. These include intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, which are induced by various inflammatory cytokines. We asked whether p-cresol alters endothelial adhesion molecule expression and modifies endothelial/leukocyte adhesion. METHODS: Human umbilical vein endothelial cells (HUVEC) were incubated with p-cresol in the presence or absence of tumor necrosis factor (TNF) or interleukin-1beta (IL-1beta). Thereafter, the endothelial molecules ICAM-1, VCAM-1, and E-selectin were quantitated and the monocyte (THP-1) adhesion to HUVEC measured. RESULTS: P-cresol decreased cytokine-induced protein and mRNA expression of ICAM-1 and VCAM-1. In addition, p-cresol significantly decreased the adhesion of THP-1 to cytokine-stimulated HUVEC. CONCLUSIONS: P-cresol may play a role in the immune defect of uremic patients by inhibiting cytokine-induced endothelial adhesion molecule expression and endothelium/monocyte adhesion. 相似文献