RESUMO
Recent work from our lab and few others have strongly suggested that immunotherapy could be an effective means of preventing the development of tau accumulation in JNPL3 transgenic mice, carrying the human P301L mutation. The aim of this study was to test the efficacy of a variety of specific tau monoclonal antibodies in JNPL3. Starting at 3 months of age, mice were treated for 4 months with weekly intraperitoneal injections of saline or purified tau monoclonal antibodies (10 mg/Kg) different in specificity for pathological tau: CP13 (pSer202), RZ3 (pThr231) and PG5 (pSer409). As expected, not all the antibodies tested showed efficacy at preventing the development of tau pathology at the described dose, with some of them even worsening the pathological scenario. Only by targeting the pSer202 epitope with CP13 was a conspicuous reduction of insoluble or soluble tau in cortex and hindbrain obtained. Here we report about the importance of screening in vivo multiple tau antibodies in order to select the antibodies to direct into future clinical studies.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Fosfo-Específicos/administração & dosagem , Imunização Passiva/métodos , Tauopatias/imunologia , Proteínas tau/genética , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Fosfo-Específicos/uso terapêutico , Modelos Animais de Doenças , Feminino , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Rombencéfalo/metabolismo , Tauopatias/genética , Tauopatias/terapia , Proteínas tau/imunologia , Proteínas tau/metabolismoRESUMO
Antiphospholipid (aPL)/anti-ß(2) glycoprotein I (anti-ß(2)GPI) antibodies stimulates tissue factor (TF) expression within vasculature and in blood cells, thereby leading to increased thrombosis. Several cellular receptors have been proposed to mediate these effects, but no convincing evidence for the involvement of a specific one has been provided. We investigated the role of Apolipoprotein E receptor 2 (ApoER2') on the pathogenic effects of a patient-derived polyclonal aPL IgG preparation (IgG-APS), a murine anti-ß(2)GPI monoclonal antibody (E7) and of a constructed dimeric ß(2)GPI I (dimer), which in vitro mimics ß(2)GPI-antibody immune complexes, using an animal model of thrombosis, and ApoER2-deficient (-/-) mice. In wild type mice, IgG-APS, E7 and the dimer increased thrombus formation, carotid artery TF activity as well as peritoneal macrophage TF activity/expression. Those pathogenic effects were significantly reduced in ApoER2 (-/-) mice. In addition, those effects induced by the IgG-APS, by E7 and by the dimer were inhibited by treatment of wild-type mice with soluble binding domain 1 of ApoER2 (sBD1). Altogether these data show that ApoER2 is involved in pathogenesis of antiphospholipids antibodies.
