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Monoclonal Anti (monoclonal + anti)
Selected Abstracts,2 -glycoprotein i is a cofactor for tissue plasminogen activator,mediated plasminogen activationARTHRITIS & RHEUMATISM, Issue 2 2009Chunya Bu Objective Regulation of the conversion of plasminogen to plasmin by tissue plasminogen activator (tPA) is critical in the control of fibrin deposition. While several plasminogen activators have been described, soluble plasma cofactors that stimulate fibrinolysis have not been characterized. The purpose of this study was to investigate the effects of ,2 -glycoprotein I (,2GPI), an abundant plasma glycoprotein, on tPA-mediated plasminogen activation. Methods The effect of ,2GPI on tPA-mediated activation of plasminogen was assessed using amidolytic assays, a fibrin gel, and plasma clots. Binding of ,2GPI to tPA and plasminogen was determined in parallel. The effects of IgG fractions and anti-,2GPI antibodies from patients with antiphospholipid syndrome (APS) on tPA-mediated plasminogen activation were also measured. Results Beta2 -glycoprotein I stimulated tPA-dependent plasminogen activation in the fluid phase and within a fibrin gel. The ,2GPI region responsible for stimulating tPA activity was shown to be at least partly contained within ,2GPI domain V. In addition, ,2GPI bound tPA with high affinity (Kd ,20 nM), stimulated tPA amidolytic activity, and caused an overall 20-fold increase in the catalytic efficiency (Kcat/Km) of tPA-mediated conversion of Glu-plasminogen to plasmin. Moreover, depletion of ,2GPI from plasma led to diminished rates of clot lysis, with restoration of normal lysis rates following ,2GPI repletion. Stimulation of tPA-mediated plasminogen activity by ,2GPI was inhibited by monoclonal anti-,2GPI antibodies as well as by anti-,2GPI antibodies from patients with APS. Conclusion These findings suggest that ,2GPI may be an endogenous regulator of fibrinolysis. Impairment of ,2GPI-stimulated fibrinolysis by anti-,2GPI antibodies may contribute to the development of thrombosis in patients with APS. [source] Beta2 -glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti,,2 -glycoprotein I autoantibodiesARTHRITIS & RHEUMATISM, Issue 4 2008Soheila Rahgozar Objective Beta2 -glycoprotein I (,2GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that ,2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of ,2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti-,2GPI antibodies was also examined. Methods HCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved ,2GPI and anti-,2GPI antibodies was determined in these systems. Results ,2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of ,2GPI at Lys317,Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti-,2GPI antibodies potentiated the procoagulant influence of ,2GPI in this system. Conclusion These novel findings suggest that ,2GPI may regulate thrombin inactivation by HCII/heparin. The observation that anti-,2GPI antibodies potentiate the protective effect of ,2GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS. [source] Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritisARTHRITIS & RHEUMATISM, Issue 6 2007Milena Pitashny Objective Pathogenic monoclonal anti,double-stranded DNA (anti-dsDNA) antibodies up-regulate the expression of lipocalin-2 in glomerular mesangial cells. This study was undertaken to investigate whether polyclonal anti-dsDNA antibodies promote the local secretion of lipocalin-2 in the kidneys of patients with systemic lupus erythematosus (SLE), and whether urinary lipocalin-2 represents a marker of kidney involvement in SLE. Methods Hispanic, African American, and white patients with SLE and normal healthy control subjects from affiliated hospitals of the Albert Einstein College of Medicine were recruited for this cross-sectional study. Patients were classified based on the presence of active renal disease according to the SLE Disease Activity Index (SLEDAI). Correlations of clinical and laboratory data with urinary and serum levels of lipocalin-2 were assessed. Results Among SLE patients, urinary lipocalin-2 levels were significantly higher in those with lupus nephritis (LN) (median 17.1 ng/mg creatinine, interquartile range [IQR] 10.3,45.4; n = 32) than in those without LN (median 11.2 ng/mg creatinine, IQR 3.1,20.3; n = 38) (P = 0.023). Compared with the values in normal controls (median 4 ng/ml, IQR 0,11.1; n = 14), urinary levels of lipocalin-2 in SLE patients were significantly higher (non-normalized median 19.3 ng/ml, IQR 8,34.2) (P = 0.004). The presence of lipocalin-2 in the urine of patients with LN correlated significantly with the renal SLEDAI score (r = 0.452, P = 0.009), but not with extrarenal disease activity. Conclusion The high prevalence of LN in SLE patients and the prognostic significance of kidney disease support the need for identifying early biomarkers to assess the risk of nephritis development and for following up patients with established disease. These findings indicate that urinary lipocalin-2 is a potential marker of the presence and severity of renal involvement in adult patients with SLE. [source] Deiminated Epstein-Barr virus nuclear antigen 1 is a target of anti,citrullinated protein antibodies in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 3 2006Federico Pratesi Objective To test the hypothesis that deimination of viral sequences containing Arg,Gly repeats could generate epitopes recognized by anti,citrullinated protein antibodies (ACPAs) that are present in rheumatoid arthritis (RA) sera. Methods Multiple antigen peptides derived from Epstein-Barr virus (EBV),encoded Epstein-Barr nuclear antigen 1 (EBNA-1) were synthesized, substituting the arginines with citrulline, and were used to screen RA sera. Anti,cyclic citrullinated peptide antibodies were purified by affinity chromatography and tested on a panel of in vitro deiminated proteins. Their ability to bind in vivo deiminated proteins was evaluated by immunoprecipitation, using EBV-infected cell lines. Results Antibodies specific for a peptide corresponding to the EBNA-135,58 sequence containing citrulline in place of arginine (viral citrullinated peptide [VCP]) were detected in 50% of RA sera and in <5% of normal and disease control sera. In addition, affinity-purified anti-VCP antibodies from RA sera reacted with filaggrin-derived citrullinated peptides, with deiminated fibrinogen, and with deiminated recombinant EBNA-1. Moreover, anti-VCP antibodies immunoprecipitated, from the lysate of calcium ionophore,stimulated lymphoblastoid cell lines, an 80-kd band that was reactive with a monoclonal anti,EBNA-1 antibody and with anti,modified citrulline antibodies. Conclusion These data indicate that ACPAs react with a viral deiminated protein and suggest that EBV infection may play a role in the induction of these RA-specific antibodies. [source] ,-catenin expression pattern and DNA image-analysis cytometry have no additional value over primary histology in clinical stage I nonseminomatous testicular cancerBJU INTERNATIONAL, Issue 3 2002J.R. Spermon Objective To determine whether the ,-catenin expression pattern and DNA content have additional value over primary tumour histology, including information on vascular invasion and tunica albuginea invasion, in detecting occult metastasis in patients with clinical stage I nonseminomatous germ cell tumours of the testis (NSGCT). Patients and methods Fifty consecutive patients with clinical stage I NSGCT underwent retroperitoneal lymphadenectomy (RPLND) between 1986 and 1992. The orchidectomy specimens were histopathologically reviewed and immunohistochemically stained with mouse monoclonal anti-,-catenin antibody. The presence of an aberrant or negative staining in >10% of the malignant cells was defined as abnormal; in all other cases tumours were classified as normal. Furthermore, intact nuclei were isolated from 50 µm thick paraffin sections of the primary tumour, Feulgen stained, and analysed with an image-analysis system. Results Of the 50 patients, 14 had positive retroperitoneal nodes (stage IIa, 28%), one pathologically staged I patient developed a lung metastasis (stage IV) within 3 months of RPLND. Univariate analysis showed that the presence of embryonal cell carcinoma, vascular invasion and tunica albuginea invasion were predictive for occult metastases. In multivariate logistic regression analysis only vascular and tunica albuginea invasion were significant. All 11 patients with no embryonal cell carcinoma in the primary tumour were classified as having pathological stage I disease. Also, the tumours which were DNA-diploid (three) or DNA-polyploid (two) were pathologically stage I. In screening for occult metastases the DNA content and the ,-catenin expression pattern had no additional value. Conclusion Vascular and tunica albuginea invasion have prognostic value in identifying patients with clinical stage I NSGCT at high risk for occult retroperitoneal disease. In contrast, the absence of embryonal cell carcinoma could predict all patients at low risk for metastasis. The DNA-ploidy also identified patients at low risk. Other DNA-analyses and the ,-catenin expression pattern provided no additional information. Further studies are recommended to identify patients who are at low or high risk for metastasis. [source] Infliximab (Remicade?) in uveitis: a reviewACTA OPHTHALMOLOGICA, Issue 2009A ABU EL ASRAR Tumor necrosis factor (TNF)-, has been implicated as an important mediator in autoimmune ocular inflammatory disease pathogenesis as shown by animal studies and its detection in the ocular fluids of patients with uveitis. Blockade of TNF-, has emerged as one of the most promising therapies in autoimmune diseases including uveitis. Currently, there are three TNF-, antagonists: two monoclonal antibodies (infliximab and adalimumab) and a soluble receptor that binds soluble TNF-, (etanercept). Infliximab is a chimeric monoclonal antibody directed against TNF-,. It binds with high affinity to both the soluble and the membrane-bound TNF-, and inhibits a broad range of biologic activities of TNF-,. Binding to membrane TNF-, can mediate programmed cell death. Several studies reported that infliximab therapy was rapidly effective and safe treatment for refractory noninfectious uveitis including childhood uveitis and is indicated as rescue therapy for relapses of ocular inflammation or as maintenance therapy when conventional immunosuppression fails. It also allowed a reduction of corticosteroids and immunosuppressive drugs required to control the disease. However, repeated infusions are required to maintain long-term remission. Moreover, infliximab administration is costly and requires hospital admission. Adalimumab, fully humanized monoclonal anti- TNF-, antibody, was also found to be effective and safe therapy for the management of refractory noninfectious uveitis. Several studies reported that infliximab was more effective than etanercept in the treatment of refractory uveitis. Perhaps infliximab's ability to target membrane-bound TNF-, in addition to the soluble form may contribute to its increased efficacy in comparison with etanercept for uveitis. [source] | ||||||||||