RESUMEN
LFA-1 (CD18,CD11a) is a cell-adhesion molecule that mediates critical immunological processes. In this paper we report the discovery and characterization of (R)-5-(4-bromobenzyl)-3-(3, 5-dichlorophenyl)-1,5-dimethylimidazolidine-2,4-dione (BIRT 377), an orally bioavailable small molecule that interacts specifically with LFA-1 via noncovalent binding to the CD11a chain and prevents LFA-1 from binding to its ligand, ICAM-1. BIRT 377 inhibits lymphocyte activity both in vitro and in vivo, in functional assays that require LFA-1-mediated cell adhesion. These results demonstrate that LFA-1-mediated leukocyte adhesion can be antagonized with noncharged, low m.w. molecules and suggest that the potential therapeutic value of adhesion inhibitors can be attained with a small, orally bioavailable compound.
Asunto(s)
Imidazoles/química , Imidazoles/farmacología , Imidazolidinas , Inmunosupresores/química , Inmunosupresores/farmacología , Antígeno-1 Asociado a Función de Linfocito/fisiología , Animales , Sitios de Unión/efectos de los fármacos , Sitios de Unión/inmunología , Adhesión Celular/efectos de los fármacos , Adhesión Celular/inmunología , Agregación Celular/efectos de los fármacos , Agregación Celular/inmunología , Femenino , Humanos , Imidazoles/aislamiento & purificación , Imidazoles/metabolismo , Inmunosupresores/aislamiento & purificación , Inmunosupresores/metabolismo , Interleucina-2/antagonistas & inhibidores , Interleucina-2/biosíntesis , Prueba de Inhibición de Adhesión Leucocitaria , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Ratones , Ratones Endogámicos BALB C , Peso Molecular , Unión Proteica/efectos de los fármacos , Unión Proteica/inmunología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Neutrophil-endothelial cell interactions are regulated by cell adhesion molecules and their cognate ligands. It has been proposed that L-selectin and Mac-1 (CD11b/CD18), two neutrophil adhesion receptors, have sequential roles in neutrophil extravasation during inflammation. In this model, L-selectin mediates rolling and initial adherence of neutrophils to endothelial cells, while Mac-1 strengthens this initial adherence and also facilitates migration of neutrophils through endothelial cells. L-selectin and Mac-1 expression are known to be inversely regulated. Here an in vitro culture system has been developed to investigate in situ expression of L-selectin during cell-to-cell interactions between neutrophils and endothelial cell monolayers by confocal immunofluorescence analysis. Neutrophils underwent profound cell shape change from round to polarized cell morphology with pseudopod formation after 5 to 15 min coculture with IL-1-stimulated human endothelial cells. L-selectin was redistributed to the pseudopod of the polarized neutrophils in correlation with such cellular changes. During initial cell attachment, neutrophils bound to IL-1-stimulated endothelial cells expressed a high level of L-selectin in a polarized pattern. L-selectin expression decreased over time during neutrophil-endothelial cell interactions.
Asunto(s)
Comunicación Celular , Endotelio Vascular/metabolismo , Selectina L/metabolismo , Neutrófilos/metabolismo , Adulto , Tamaño de la Célula , Células Cultivadas , Técnicas de Cocultivo , Endotelio Vascular/efectos de los fármacos , Humanos , Interleucina-1/farmacología , Microscopía Confocal , Microscopía Fluorescente , Neutrófilos/citología , Factores de TiempoRESUMEN
BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is believed to play a role in acute rejection of allografted tissues. This molecule is involved in the interaction of T cells with antigen-presenting cells expressed on the vascular endothelium of transplanted organs and is involved in the adhesion of inflammatory cells to this endothelium and their subsequent migration into the underlying tissues. METHODS: Rat abdominal heterotopic heart transplantation was used to study the role of ICAM-1 in the rejection process. American Cancer Institute rats were used as donors; Lewis rats were used as recipients. Graft survival was monitored daily via donor heart palpation. Nine groups (n = 6/group) were studied: untreated controls; olive oil; cyclosporine at 1.5, 2.75, and 5.0 mg/kg, respectively; R3.1, a control monoclonal antibody; 1A29, a rat anti-ICAM-1 monoclonal antibody, 3 mg/kg administered intraperitoneally; a combination of 1A29 (3 mg/kg) and cyclosporine (1.5 mg/kg); and a combination of 1A29 (3 mg/kg) and cyclosporine (2.75 mg/kg). RESULTS: Mean rejection time was 8.8 +/- 0.6 days for the untreated allografted controls and 9.7 +/- 1.1 days for the olive oil controls. Cyclosporine (1.5, 2.75, and 5.0 mg/kg) showed mean rejection times of 8.5 +/- 0.3, 20.5 +/- 1.9, and 28.8 +/- 3.6 days, respectively. The 1A29 treatment showed a mean rejection time of 9.3 +/- 0.7 days. Combination therapy of 1A29 and cyclosporine at 1.5 or 2.75 mg/kg demonstrated mean rejection times of 17.7 +/- 3.3 and 29.2 +/- 6.7 days, respectively. Thus 1A29 alone does not prolong cardiac allograft survival; however, combination therapy with either a subthreshold or a moderate dose of cyclosporine significantly extends the time to rejection of heterotopically transplanted rat hearts. CONCLUSIONS: Although monotherapy with an ICAM-1 antagonist alone may not be beneficial in preventing acute rejection episodes after organ transplantation, combination therapy of an anti-ICAM-1 monoclonal antibody may allow for a reduction in the dose of cyclosporine necessary for immune suppression. Such a reduction could lead to a lowering of the incidence of nephrotoxicity and other side effects associated with long-term cyclosporine administration.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Ciclosporina/administración & dosificación , Rechazo de Injerto/prevención & control , Trasplante de Corazón , Inmunosupresores/administración & dosificación , Molécula 1 de Adhesión Intercelular/inmunología , Abdomen , Animales , Anticuerpos Monoclonales/inmunología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Rechazo de Injerto/inmunología , Supervivencia de Injerto/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Linfocitos T/inmunología , Trasplante Heterotópico , Trasplante HomólogoAsunto(s)
Molécula 1 de Adhesión Intercelular/biosíntesis , Terapia PUVA , Psoriasis/tratamiento farmacológico , Psoriasis/radioterapia , Terapia Ultravioleta , Adulto , Anciano , Dermatología/métodos , Ensayo de Inmunoadsorción Enzimática , Humanos , Molécula 1 de Adhesión Intercelular/análisis , Persona de Mediana Edad , Pronóstico , Psoriasis/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
Atherosclerosis is increasingly thought to be a chronic inflammatory disease. Inflammation requires transmigration of leukocytes from the circulation to the tissues. Adhesion of leukocytes to endothelial calls is the initial event in an inflammatory response and is mediated by expression of several adhesion molecules. In this study we characterize the contribution of intercellular adhesion molecules (ICAM-1) and L-selectin in patients with different coronary artery disease syndromes. Serum concentrations of cICAM-1 and sL-selectin were measured by enzyme-linked immunosorbent assay in 31 patients with stable angina, 30 patients with unstable angina, 18 patients with acute myocardial infarction and 20 healthy subjects in a control group. All patients underwent coronary angiography. Mean (+/-SE) cICAM-1 levels were higher (p < 0.05) in patients with stable angina (249 +/- 6 ng/ml), unstable angina (260 +/- 16 ng/ml), or acute myocardial infarction (261 +/- 24 ng/ml) compared with those in subjects in the control group (171 +/- 11 ng/ml). In contrast, levels of sL-selectin were lower (p < 0.01) in patients with stable angina (1.2 +/- 0.1 microg/ml), unstable angina (1.1 +/- 0.6 microg/ml), or acute myocardial infarction (1.1 +/- 0.1 microg/ml) compared with those in subjects in the control group (1.8 +/- 0.1 microg/ml). No difference was found in cICAM-1 or sL-selectin levels among patients with stable angina, unstable angina, or acute myocardial infarction. No correlation was seen between cICAM-1 or sL-selectin levels and extent (or severity) of coronary artery disease or leukocyte count. L-selectin expression was observed to be depressed in patients with severe angina compared with that in members of the control group. To examine the mechanism of reduction in sL-selectin levels and L-selectin expression on leukocytes, leukocytes from the control group were stimulated in vitro. Stimulation of leukocytes resulted in a rapid downregulation of surface L-selectin expression, measured by flowcytometry, similar to the suppressed expression of L-selectin found on leukocytes from patients with coronary artery disease. In conclusion, altered cICAM-1 and sL-selectin levels in patients with coronary artery disease reflect the presence of a chronic inflammatory process. This inflammatory process results in downregulation of leukocyte expression of L-selectin and thus lower circulating sL-selectin levels.
Asunto(s)
Molécula 1 de Adhesión Intercelular/sangre , Selectina L/sangre , Isquemia Miocárdica/sangre , Angina de Pecho/sangre , Angina Inestable/sangre , Adhesión Celular , Movimiento Celular , Enfermedad Crónica , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/sangre , Enfermedad Coronaria/sangre , Regulación hacia Abajo , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica , Humanos , Inflamación , Selectina L/genética , Recuento de Leucocitos , Leucocitos/metabolismo , Leucocitos/patología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangreRESUMEN
Intercellular adhesion molecule-1 (ICAM-1, CD54) is upregulated in many cell types stimulated by cytokines. A human hepatoblastoma cell line (C3A, a subclone of HepG2/C3 that is currently being used as a surrogate liver) and human lung adenocarcinoma cells (A549) were stimulated with interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), or IL-6 to determine any differences in cell type responsiveness to individual cytokines for ICAM-1 upregulation. Time courses were performed with each cytokine evaluating ICAM-1 mRNA, surface expression, and cICAM-1 in the cell culture media. Between 3 and 6 hours, IL-1 beta (30 U/mL) stimulated the greatest increase in hepatocyte ICAM-1 mRNA, followed by IFN gamma (100 U/ mL), and IL-6 (100 U/mL) in order of potency. Except for IL-6, cytokine-induced hepatocyte surface levels of ICAM-1 (immunofluorescence flow cytometry, mAb R6.5) were dose dependent, with inhibition at higher concentration. Highest levels followed stimulation with INF gamma (P < .05). Significantly less was found after both IL-1 beta and TNF alpha; none was detected after IL-6 (P < .05). In contrast, IL-1 beta stimulated significantly more cICAM-1 release from hepatocytes than the other cytokines (P < .001), and IL-6 stimulated modest cICAM-1. Between 3 and 6 hours in the A549 cells, IL-1 beta stimulated the greatest increase in ICAM-1 mRNA, followed by TNF alpha. Both responses were greater than that observed in the hepatocytes. IFN gamma- and IL-6-induced ICAM-1 mRNA synthesis was not different from unstimulated A549 cells. Cytokine-induced A549 surface levels of ICAM-1 (immunofluorescence flow cytometry, mAb R6.5) was highest for IL-1 beta (peak levels similar to hepatocyte response), modest with TNF alpha (peak levels less than hepatocytes), detectable with IFN gamma (much less than hepatocytes), and nondetectable after IL-6. No ICAM-1 release from A549 cells was induced under any condition. In hepatocytes the amount of ICAM-1 mRNA was best accounted for by considering both cell surface levels of ICAM-1 and cICAM-1 levels. In human lung adenocarcinoma cells, the cytokine induction of ICAM-1 mRNA could potentially be accounted for by observing cell surface levels of ICAM-1 because no cICAM-1 was produced. These results suggest that surface ICAM-1 and cICAM-1 may be differentially controlled by each cytokine and by each parenchymal cell type.
Asunto(s)
Citocinas/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Medios de Cultivo/metabolismo , Relación Dosis-Respuesta a Droga , Hepatoblastoma/metabolismo , Hepatoblastoma/patología , Humanos , Inmunohistoquímica , Molécula 1 de Adhesión Intercelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , ARN Mensajero/metabolismo , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
Soluble adhesion protein intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule (E-selectin) were measured in serum and cerebrospinal fluid (CSF) of patients with relapsing-remitting multiple sclerosis (RRMS) in remission and in exacerbation, as well as patients with chronic progressive MS, stable MS, and in patients with other neurological and inflammatory diseases (ONDs). Serum ICAM-1 and E-selectin were significantly elevated in patients with MS over those with ONDs and controls. CSF VCAM-1 and E-selectin were found to be elevated over control and disease control samples. No increase in CSF ICAM-1 was observed. Results were analyzed longitudinally and by MS category. In paired CSF and serum samples from patients in exacerbation, elevated VCAM-1 correlated with increased serum VCAM-1 in 5 of 7 patients. Elevated CSF E-selectin did not correlate with elevations in serum E-selectin.
Asunto(s)
Moléculas de Adhesión Celular/análisis , Molécula 1 de Adhesión Intercelular/análisis , Esclerosis Múltiple/sangre , Esclerosis Múltiple/líquido cefalorraquídeo , Análisis de Varianza , Adhesión Celular/fisiología , Enfermedad Crónica , Selectina E , Humanos , Estudios Longitudinales , Esclerosis Múltiple/clasificación , Enfermedades del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Molécula 1 de Adhesión Celular VascularRESUMEN
L-selectin is a lectin cell adhesion molecule expressed on the cell surfaces of lymphocytes, monocytes and granulocytes. Upon leukocyte activation or L-selectin cross-linking the transmembrane-bound L-selectin is rapidly shed from the cell surface. Based on these observations, it has been proposed that L-selectin is proteolytically cleaved from the cell surface. However a panel of common protease inhibitors have no effect on L-selectin proteolysis. To further define the mechanism of L-selectin down-regulation we have produced reagents to study proteolytic fragments of L-selectin. We have developed a trapping ELISA for the detection of soluble L-selectin. In addition we have produced a high affinity polyclonal antisera against the extracellular domain and against the cytoplasmic domain of L-selectin. Both antisera immunoprecipitate the intact form of L-selectin from metabolically labeled PHA lymphoblasts and peripheral blood neutrophils. We review here our progress in defining a 6 kD L-selectin transmembrane peptide (L-STMP) from PMA activated lymphoblasts and fMLP-activated neutrophils. Radiochemical sequencing data indicate that the cleavage site occurs between Lys321 and Ser322 in a short membrane-proximal region of the extracellular domain.
Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Membrana Celular/enzimología , Endopeptidasas/metabolismo , Secuencia de Aminoácidos , Anticuerpos Monoclonales , Moléculas de Adhesión Celular/análisis , Moléculas de Adhesión Celular/química , Ensayo de Inmunoadsorción Enzimática , Humanos , Técnicas de Inmunoadsorción , Selectina L , Activación de Linfocitos , Linfocitos/metabolismo , Datos de Secuencia Molecular , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/metabolismo , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/farmacología , Homología de Secuencia , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Noninvasive methods to assess immune activation would be helpful in optimizing therapy after heart transplantation to reduce rejection (acute and chronic) and complications caused by excessive immunosuppressive therapy. Intercellular adhesion molecule 1 has been shown to play an important role in T-cell activation and allograft rejection. A soluble form of intercellular adhesion molecule 1 has been discovered to be circulating in plasma. To test the hypothesis that increased levels of circulating intercellular adhesion molecule 1 may have prognostic value as a marker of immune activation, we examined whether levels of circulating intercellular adhesion molecule 1 during the early postoperative period correlated with endomyocardial biopsy scores, soluble interleukin-2 receptor levels, human leukocyte antigen mismatch, and survival. For the first 3 weeks after surgery, serum was obtained once weekly on the same day as endomyocardial biopsy samples from 52 patients who survived more than 30 days after heart transplantation. A sandwich enzyme-linked immunosorbent assay was used to measure circulating intercellular adhesion molecule 1 and soluble interleukin-2 receptor. Increased circulating intercellular adhesion molecule 1 levels did not correlate with endomyocardial biopsy scores but were associated with greater mismatch at the human leukocyte antigen-B and -DR loci (p = 0.02). A significant correlation was found (p = 0.002) between circulating intercellular adhesion molecule 1 levels and soluble interleukin-2 receptor, albeit with a low r value of 0.27. Survival was reduced in patients with high levels of circulating intercellular adhesion molecule 1 (p = 0.006) or soluble interleukin-2 receptor (p = 0.001) with the greatest reduction in survival when both were elevated.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Trasplante de Corazón/inmunología , Prueba de Histocompatibilidad , Molécula 1 de Adhesión Intercelular/sangre , Biopsia , Endocardio/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Rechazo de Injerto/diagnóstico , Trasplante de Corazón/mortalidad , Humanos , Inmunosupresores/uso terapéutico , Tablas de Vida , Masculino , Persona de Mediana Edad , Miocardio/patología , Pronóstico , Receptores de Interleucina-2/análisis , Factores de TiempoRESUMEN
Cell adhesion molecules were first described as accessory molecules simply to bridge one cell to another. More recently, it has been realized that these molecules also transmit signals from outside of the cell to inside. We show that cross-linking of the ICAM-1 on the cell membrane with anti-ICAM-1 mAb and F(ab')2 fragments of goat anti-MIgG in the presence of suboptimal levels of the bacterial peptide FMLP results in co-stimulation of an oxidative burst from CD14 expressing PBMCs. The amplitude of the oxidative response was less than the oxidative burst induced by CD18 cross-linking, whereas the response was more prolonged. On the other hand, cross-linking by anti-L-selectin mAb plus F(ab')2 fragments of goat anti-MIgG induced a minimal oxidative burst that was not significantly greater than the response generated by anti-L-selectin mAb alone. The addition of an excess of soluble ICAM-1 to compete for the anti-ICAM-1 mAb inhibits the oxidative burst in response to ICAM-1 cross-linking but not to CD18 cross-linking. These results suggest that ICAM-1 is capable of delivering a transmembrane signal into CD14-positive PBMC.
Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Leucocitos Mononucleares/metabolismo , Estallido Respiratorio , Animales , Anticuerpos Monoclonales , Antígenos CD , Antígenos de Diferenciación Mielomonocítica , Antígenos CD18 , Adhesión Celular , Moléculas de Adhesión Celular/inmunología , Reactivos de Enlaces Cruzados , Cabras , Humanos , Fragmentos Fab de Inmunoglobulinas , Técnicas In Vitro , Molécula 1 de Adhesión Intercelular , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Receptores de Lipopolisacáridos , N-Formilmetionina Leucil-Fenilalanina/farmacología , Estallido Respiratorio/efectos de los fármacos , Transducción de SeñalRESUMEN
OBJECTIVE: Our purpose was to determine if circulating intercellular adhesion molecule-1, a marker of chronic inflammation, is present in amniotic fluid in midtrimester, is increased in patients with elevated maternal serum alpha-fetoprotein level, and is associated with intrauterine growth retardation. STUDY DESIGN: Amniotic fluid circulating intercellular adhesion molecule-1 levels were assayed by enzyme-linked immunoassay in 273 samples obtained by midtrimester amniocentesis in gestations involving a single, structurally normal fetus. The control group consisted of 108 patients with normal maternal serum alpha-fetoprotein levels and 165 patients with elevated levels. Intrauterine growth retardation was diagnosed if birth weight was < 10th percentile for the clinically estimated gestational age. RESULTS: Circulating intercellular adhesion molecule-1 was detectable in amniotic fluid in 105 of 273 samples (38%). In the control group it was detectable in amniotic fluid in seven of 108 (6%). In patients with elevated maternal serum alpha-fetoprotein 97 of 164 (59%) had detectable levels (p < 0.001). Of the 273 cases 38 (14%) had intrauterine growth retardation. Of these 23 (59%) had detectable circulating intercellular adhesion molecule-1 levels (p < 0.001). Of the seven cases of intrauterine growth retardation with normal maternal serum alpha-fetoprotein levels, one (14%) had detectable circulating intercellular adhesion molecule-1. Of the 31 cases of intrauterine growth retardation with elevated maternal serum alpha-fetoprotein 22 (71%) had detectable circulating intercellular adhesion molecule-1. When circulating intercellular adhesion molecule-1 was detectable in amniotic fluid, increasing levels was significantly related to decreasing gestational age at delivery (p < 0.005). CONCLUSIONS: Midtrimester amniotic fluid from normal pregnancies does not generally contain detectable circulating intercellular adhesion molecule-1. Detectable amniotic fluid levels are significantly related to a birth weight < 10th percentile at delivery and to elevated midtrimester maternal serum alpha-fetoprotein levels. Increasing circulating intercellular adhesion molecule-1 levels are related to shortened length of gestation. This test may contribute to risk assessment for intrauterine growth retardation and prematurity. Circulating intercellular adhesion molecule-1 is a known marker of inflammatory processes; its further study may also improve understanding of the pathophysiologic mechanisms of certain cases of intrauterine growth retardation and prematurity.
Asunto(s)
Líquido Amniótico/química , Antígenos CD/análisis , Moléculas de Adhesión Celular/análisis , Retardo del Crecimiento Fetal/diagnóstico , Diagnóstico Prenatal , alfa-Fetoproteínas/análisis , Biomarcadores , Peso al Nacer , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Molécula 1 de Adhesión Intercelular , Embarazo/sangre , Segundo Trimestre del EmbarazoRESUMEN
OBJECTIVE: We sought to assess whether circulating levels of intercellular adhesion molecule 1 (ICAM-1) in patients with rheumatoid arthritis (RA) are elevated and correlate with clinical measures of disease activity and whether this ICAM-1 originates from the synovium. METHODS: Circulating ICAM-1 (cICAM-1) levels were determined by sandwich enzyme-linked immunosorbent assay of serum from 61 RA, 18 osteoarthritis (OA), and 11 inflammatory arthritis (IA) patients. In addition, paired serum and synovial fluid samples were collected from 17 RA, 9 OA, and 4 IA patients. The stability of cICAM-1 was assessed by overnight incubation at 37 degrees C. Finally, the potential degradative effects of synovial fluid proteases were assessed by incubation of recombinant soluble ICAM-1 with patient synovial fluid. RESULTS: RA sera contained significantly greater (P < 0.001) levels of cICAM-1 compared with RA synovial fluid and compared with sera or synovial fluid from the OA and IA patients. Circulating ICAM-1 levels were unaffected by overnight incubation at 37 degrees C and were unaffected by exposure to RA, OA, or IA synovial fluid. Serum levels of cICAM-1 demonstrated a weak, but significant (P < 0.05) correlation with the joint score and erythrocyte sedimentation rate in 25 RA patients treated with nonsteroidal antiinflammatory drugs. CONCLUSION: The greatest elevations of cICAM-1 were seen in RA patient sera. In both RA and OA, synovial fluid cICAM-1 levels were consistently lower than serum levels, suggesting that cICAM-1 did not originate in the synovium. Because the production of cICAM-1 can be increased by cytokines (e.g., interleukin-1, tumor necrosis factor alpha), elevated levels of circulating ICAM-1 in RA may be reflective of systemic exposure to elevated cytokine levels.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Reumatoide/sangre , Moléculas de Adhesión Celular/análisis , Osteoartritis/sangre , Líquido Sinovial/química , Anciano , Artritis Reumatoide/tratamiento farmacológico , Moléculas de Adhesión Celular/sangre , Femenino , Humanos , Molécula 1 de Adhesión Intercelular , Masculino , Persona de Mediana Edad , Osteoartritis/tratamiento farmacológico , Índice de Severidad de la Enfermedad , TemperaturaRESUMEN
To examine whether changes in leukocyte adhesion properties occur during stroke, we measured circulating serum intercellular adhesion molecule 1 (cICAM-1) levels and neutrophil adhesion in acute stroke, patients at high risk of stroke, and in matched controls. Levels of cICAM-1 were significantly lower in the stroke group (186.2 +/- 15.6 ng ml-1) compared to controls (257.7 +/- 24.8) and risks (257.7 +/- 16.5). Neutrophil adhesion was significantly higher in the stroke group (23.6 +/- 4.3%; n = 14) compared to controls (9.7 +/- 2.3%; n = 12) and risks (12.7 +/- 2.5%; n = 13). These data suggest that changes in leukocyte adhesion dynamics are occurring in acute stroke.
Asunto(s)
Moléculas de Adhesión Celular/sangre , Trastornos Cerebrovasculares/sangre , Neutrófilos/fisiología , Adhesión Celular , Humanos , Molécula 1 de Adhesión Intercelular , Laminina , Factores de RiesgoRESUMEN
The adhesion molecule ICAM-1 mediates leucocyte adhesion to target structures and other immune cells by binding with the leucocyte adhesion receptors LFA-1 and MAC-1. During rejection of human liver transplants there is increased expression of ICAM-1 on target structures such as bile ducts and venous endothelium and also on lymphocytes infiltrating the graft. Recent reports suggest that a soluble, functionally active form of ICAM-1 designated circulating ICAM-1 (cICAM-1) is released by activated lymphocytes and might be an important mechanism for modulating lymphocyte adhesion and the inflammatory process. We detected cICAM-1 in bile and serum after liver transplantation using an enzyme-linked immunosorbent assay. Serum cICAM-1 was elevated early in the course of acute rejection and appeared at the same time as the soluble interleukin-2 receptor, a marker of lymphocyte activation. Serum levels, however, were not specific for rejection since they were also elevated in infective complications. In contradistinction, biliary levels of cICAM-1 were only elevated in rejection and appeared to be due to local release/secretion within the liver. These data demonstrate that cICAM-1 is released within the liver during graft rejection, probably from activated lymphocytes, and support previous studies that suggested that factors in bile reflect immunological activity within the liver graft more closely than serum factors.
Asunto(s)
Bilis/química , Moléculas de Adhesión Celular/metabolismo , Rechazo de Injerto/sangre , Trasplante de Hígado , Hígado/metabolismo , Colangitis/sangre , Humanos , Molécula 1 de Adhesión Intercelular , Sepsis/sangreRESUMEN
Serum levels of recently discovered circulating forms of adhesion molecules, ICAM-1 and L-selectin, were found to be elevated in IDDM patients and in subjects at risk for developing IDDM compared with 100 normal, nondiabetic blood donors. Both adhesion molecules were determined by sandwich ELISA. Serum concentrations of either clCAM-1 or cL-selectin were > 2SD of normal mean in 10 of 14 recent-onset IDDM patients (P < 0.05). Serum levels of clCAM-1 and cL-selectin did not correlate. In first-degree relatives, elevated adhesion molecule levels were observed in the 6 ICA+ individuals and in the ICA- individuals all (n = 14) with a genetic risk of IDDM (sharing HLA-DR3 and/or-DR4 with the diabetic relative) but not in the HLA-DR3- and/or -DR4- relatives (n = 13). We conclude that elevated clCAM-1 and cL-selectin levels occur independently of ICA status and probably reflect ongoing immune processes in recent-onset IDDM patients and first-degree relatives at risk for IDDM.
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Moléculas de Adhesión Celular/sangre , Diabetes Mellitus Tipo 1/genética , Adulto , Antígenos CD/sangre , Autoanticuerpos/sangre , Biomarcadores/sangre , Niño , Diabetes Mellitus Tipo 1/epidemiología , Familia , Femenino , Humanos , Molécula 1 de Adhesión Intercelular , Islotes Pancreáticos/inmunología , Selectina L , Masculino , Glicoproteínas de Membrana/sangre , Valores de Referencia , Factores de RiesgoAsunto(s)
Antígenos CD , Moléculas de Adhesión Celular/sangre , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto/sangre , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Paraparesia Espástica Tropical/sangre , Paraparesia Espástica Tropical/diagnóstico , Sialoglicoproteínas/sangre , Biomarcadores/sangre , Biomarcadores de Tumor/sangre , Portador Sano , Diagnóstico Diferencial , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Molécula 1 de Adhesión Intercelular , Leucosialina , Sondas de OligonucleótidosRESUMEN
The leucocyte adhesion molecule intercellular adhesion molecule-1 is induced on bile ducts in patients with primary biliary cirrhosis and primary sclerosing cholangitis and may be involved in targeting immune damage to these structures. It has recently been reported that, when activated, in vitro lymphocytes release a soluble form of intercellular adhesion molecule-1 that can also be detected in human serum. Because it is functionally active, this circulating intercellular adhesion molecule-1 might play a role in regulating inflammation by blocking adhesion. We used an enzyme-linked immunosorbent assay to detect circulating intercellular adhesion molecule-1 in the serum of patients with primary biliary cirrhosis and primary sclerosing cholangitis. Levels of circulating intercellular adhesion molecule-1 were markedly elevated in primary biliary cirrhosis and primary sclerosing cholangitis when compared with other chronic liver diseases. Circulating intercellular adhesion molecule-1 is probably derived from activated lymphocytes rather than from bile ducts because biliary epithelial cells from patients with primary biliary cirrhosis did not release circulating intercellular adhesion molecule-1 when stimulated to express the membrane-bound molecule in vitro. These studies are the first to demonstrate circulating intercellular adhesion molecule-1 in chronic inflammatory diseases that are characterized by strong tissue expression of intercellular adhesion molecule-1 and as such suggest a potential immunoregulatory role for circulating adhesion molecules. The very high levels detected in primary biliary cirrhosis and primary sclerosing cholangitis probably reflect lymphocyte activation, which is further evidence of immune pathogeneses for these diseases.
Asunto(s)
Moléculas de Adhesión Celular/sangre , Colangitis Esclerosante/sangre , Cirrosis Hepática Biliar/sangre , Bilirrubina/sangre , Biomarcadores , Biopsia , Femenino , Humanos , Molécula 1 de Adhesión Intercelular , Hígado/patología , Cirrosis Hepática Biliar/patología , Activación de Linfocitos , MasculinoRESUMEN
A circulating form of the usually membrane-bound intercellular adhesion molecule-1 (ICAM-1) was identified and characterized in normal human serum, and in sera from patients with leukocyte adhesion deficiency (LAD). The molecule, designated circulating ICAM-1 (cICAM-1) was detected and quantitated by sandwich ELISA. Levels of cICAM-1 in sera from normal individuals ranged from 100 to 200 ng/ml. Sera from LAD patients had elevated cICAM-1 levels ranging from 200 to 700 ng/ml. The elevated levels of cICAM-1 in LAD sera may be due to an inability to adsorb cICAM-1 to cell-bound LFA-1 or may be an indirect result of the pathology accompanying the syndrome. cICAM-1 bound to mAb specific for four distinct ICAM-1 epitopes localized in domains D1, D2, D4, and D5, and displayed similar molecular size properties as recombinant soluble ICAM-1 on FPLC size-exclusion chromatography. When immobilized via a domain D5-specific mAb, cICAM-1 mediated function (LFA-1)-dependent lymphocyte adhesion equivalent to sICAM-1. These data indicate that cICAM-1 contains most, if not all, of the five extracellular domains of membrane ICAM-1, as well as the ability to bind specifically to LFA-1. The cellular source of cICAM-1 appeared to be from mononuclear cells; only lymphoid cell lines or primary PBMC cultures had detectable levels of cICAM-1 in cell culture supernatants. Because cICAM-1 retains the ability to bind specifically to LFA-1, it may act to regulate cell adhesion by promoting de-adhesion. Alternatively, cICAM-1 may be the indirect consequence of inflammation or tissue damage. As such, the detection of cICAM-1 could be useful as a marker of inflammatory disease.
Asunto(s)
Antígenos CD/metabolismo , Moléculas de Adhesión Celular/sangre , Antígenos CD18 , Adhesión Celular , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Clonación Molecular , Análisis Mutacional de ADN , Humanos , Técnicas In Vitro , Molécula 1 de Adhesión Intercelular , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Estructura Molecular , Peso Molecular , SolubilidadRESUMEN
Current reports have suggested a role for intracellular adhesion molecule 1 (ICAM-1) in the progression of human malignant melanoma and other cancers. Stage I, II, and III patients with histologically diagnosed malignant melanoma had significantly increased serum levels of circulating ICAM-1 (cICAM-1) and a striking increase in the incidence of positive sera. In Stage II and III patients, the level of cICAM-1 was inversely correlated with survival. Patients with elevated levels of serum cICAM-1 (greater than 2 SD units above control mean) had a significantly shorter mean survival. We suggest that elevated levels of serum cICAM-1 may be of diagnostic and prognostic importance in patients with malignant cutaneous melanoma.