Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII

Factor VIII (FVIII) inhibitors are anti-FVIII IgG that arise in up to 50% of the patients with hemophilia A, upon therapeutic administration of exogenous FVIII. Factor VIII inhibitors neutralize the activity of the administered FVIII by sterically hindering its interaction with molecules of the coagulation cascade, or by forming immune complexes with FVIII and accelerating its clearance from the circulation. We have shown previously that a subset of anti-factor VIII IgG hydrolyzes FVIII. FVIII-hydrolyzing IgG are detected in over 50% of inhibitor-positive patients with severe hemophilia A, and are not found in inhibitornegative patients. Although human proficient catalytic Abs have been described in a number of inflammatory and autoimmune disorders, their pathological relevance remains elusive. We demonstrate here that the kinetics of FVIII degradation by FVIIIhydrolyzing IgG are compatible with a pathogenic role for IgG catalysts. We also report that FVIII-hydrolyzing IgG from each patient exhibit multiple cleavage sites on FVIII and that, while the specificity of cleavage varies from one patient to another, catalytic IgG preferentially hydrolyze peptide bonds containing basic amino acids

Anticorps anti-facteur VIII chez l'homme sain et en pathologie

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Antibody-based therapies for COVID-19: Can Europe move faster?

Michel Goldman and colleagues call on the European medical and scientific community to coordinate efforts on immunotherapy-based approaches to coronavirus

DC-SIGN and alpha 2,6-sialylated IgG Fc interaction is dispensable for the anti-inflammatory activity of IVIg on human dendritic cells

Intravenous immunoglobulin (IVIg) is widely used to treat autoimmune diseases. Several mutually nonexclusive mechanisms are proposed to explain the beneficial effects of IVIg in patients (1, 2). Lately, Ravetch and colleagues (3) demonstrate that anti-inflammatory activity of IVIg is mediated mainly by antibodies that contain terminal _2,6-sialic acid linkages at the Asn297-linked glycan of Fc region

Controlling HIV among people who inject drugs in Eastern Europe and Central Asia: insights from modeling.

BACKGROUND: Although there is evidence of the effectiveness of needle and syringe programme (NSP), opioid substitution therapy (OST) and antiretroviral therapy (ART) in reducing HIV prevalence, most Central and Eastern European sub-regions still have low or no coverage of most or all of these interventions. METHODS: We conducted a modelling analysis to consider the potential impact on HIV incidence and prevalence of OST, NSP and ART in three illustrative epidemic scenarios: Russia (St. Petersburg); Estonia (Tallinn) and Tajikistan (Dushanbe). For each intervention, we consider the coverage needed of each intervention separately or in combination to: (1) achieve a 30% or 50% relative reduction in HIV incidence or prevalence over 10 years; and (2) reduce HIV incidence to below 1% or HIV prevalence below 10% after 20 years. A sensitivity analysis for St. Petersburg considered the implications of greater on no risk heterogeneity, none or more sexual HIV transmission, like-with-like mixing, different injecting cessation rates and assuming a lower HIV acute phase cofactor. RESULTS: For St. Petersburg, when OST, NSP and ART are combined, only 14% coverage of each intervention is required to achieve a 30% reduction in HIV incidence over 10 years. Similar findings are obtained for Tallinn and Dushanbe. In order to achieve the same reductions in HIV prevalence over 10 years, over double the coverage level is required relative to what was needed to achieve the same reduction in HIV incidence in that setting. To either reduce HIV incidence to less than 1% or HIV prevalence to less than 10% over 20 years, with all interventions combined, projections suggest that very high coverage levels of 74–85% are generally required for the higher prevalence settings of Tallinn and St. Petersburg, whereas lower coverage levels (23–34%) are needed in Dushanbe. Coverage requirements are robust to increased sexual HIV transmission, risk heterogeneity and like-with-like mixing, as well as to assuming a lower HIV acute phase cofactor or different injecting cessation rate. CONCLUSION: The projections suggest that high but achievable coverage levels of NSP can result in large decreases (30%) in HIV incidence in settings with high HIV prevalence among PWID. Required coverage levels are much lower when interventions are combined or in lower prevalence settings. However, even when all three interventions are combined, the targets of reducing HIV incidence to less than 1% or prevalence to less than 10% in 20 years may be hard to achieve except in lower prevalence settings