RESUMO
Therapeutic agents currently in use to treat systemic lupus erythematosus (SLE) are predominantly immunosuppressive agents with limited specificities. Multiple groups, including ours, have illustrated that inducing tolerance in SLE animal models ameliorates disease symptoms and increases survival. We examined if oral administration of a tolerogenic peptide could affect SLE disease progression. The pConsensus (pCons) peptide, based on protein sequences of anti-double stranded (anti-ds)DNA antibodies, induces tolerance through upregulation of regulatory T cells when administered intravenously. Six different forms of pCons, including multiple antigenic peptides (MAP) and cyclic peptides made up of L- and D-amino acids, at three different concentrations, were fed to BWF1 SLE-susceptible mice for 30 weeks. Mice fed 100 µg of L-MAP or D-MAP had less cumulative proteinuria and serum anti-dsDNA antibody levels than controls. In addition, animals in these groups also survived significantly longer than controls with a corresponding increase in serum transforming growth factor beta (TGFß, implying a protective role for pCons-induced regulatory T cells. Oral administration of a tolerogenic peptide is a safe, effective method for ameliorating SLE disease manifestations and prolonging survival in SLE-prone mice. Induction of oral tolerance using modified pCons peptides could lead to a novel targeted therapy for human SLE.
Assuntos
Anticorpos Antinucleares/biossíntese , Tolerância Imunológica/imunologia , Imunossupressores , Lúpus Eritematoso Sistêmico , Nefrite/tratamento farmacológico , Peptídeos , Administração Oral , Animais , Anticorpos Antinucleares/sangue , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Nefrite/patologia , Nefrite/fisiopatologia , Compostos Orgânicos , Peptídeos/administração & dosagem , Peptídeos/imunologia , Peptídeos/uso terapêutico , Taxa de Sobrevida , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/imunologiaRESUMO
In human hosts and in murine models, the immune response to Strongyloides spp. is Th2 type. In addition, the profile of the host immune response follows various symptoms induced by Strongyloides spp. In the present study, we demonstrated that the L2 and L49 strains of Strongyloides venezuelensis obtained from Bolomys lasiurus and Nectomys squamipes induced significant and similar increases in eosinophil/mononuclear cell counts in the blood, peritoneal cavity fluid and bronchoalveolar lavage fluid when compared with uninfected mice. However, in the first 3 days of infection, IL-4, IL-5 and IFN-gamma levels were higher in the lungs of mice infected with the L2 strain, which also presented greater production of IgG and IgG1 than did mice infected with the L49 strain. The higher antibody and cytokine levels induced by the L2 strain correlated with a decrease in the number of female parasites recovered in the faeces of mice on post-infection day 7. The results demonstrate that the L2 strain was a more potent stimulant of the humoral immune response, which can result in more efficient antibody-dependent cell-mediated cytotoxicity, a mechanism involved in eosinophil activation and parasite elimination. Further studies are needed in order to elucidate the molecular differences among parasites.
Assuntos
Strongyloides/imunologia , Estrongiloidíase/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Eosinófilos/imunologia , Interferon gama/imunologia , Larva/imunologia , Pulmão/imunologia , Pulmão/parasitologia , Masculino , Camundongos , Contagem de Ovos de Parasitas , Ratos , Ratos Wistar , Roedores , Strongyloides/classificação , Strongyloides/crescimento & desenvolvimento , Strongyloides/isolamento & purificação , Estrongiloidíase/sangue , Estrongiloidíase/parasitologia , Zoonoses/parasitologiaAssuntos
Anticorpos Antiprotozoários/sangue , Doenças do Cão/sangue , Ensaio de Imunoadsorção Enzimática/veterinária , Proteínas de Protozoários/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Animais , Antígenos de Protozoários/imunologia , Antígenos de Superfície/imunologia , Western Blotting/veterinária , Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Cães , Ensaio de Imunoadsorção Enzimática/métodos , Imunoglobulina G/sangue , Curva ROC , Sensibilidade e Especificidade , Toxoplasmose Animal/diagnósticoRESUMO
Host cell invasion by Toxoplasma gondii is a multistep process with one of the first steps being the apical release of micronemal proteins that interact with host receptors. We demonstrate here that micronemal protein 1 (MIC1) is a lactose-binding lectin. MIC1 and MIC4 were recovered in the lactose-eluted (Lac(+)) fraction on affinity chromatography on immobilized lactose of the soluble antigen fraction from tachyzoites of the virulent RH strain. MIC1 and MIC4 were both identified by N-terminal microsequencing. MIC4 was also identified by sequencing cDNA clones isolated from an expression library following screening with mouse polyclonal anti-60/70 kDa (Lac(+) proteins) serum. This antiserum localized the Lac(+) proteins on the apical region of T. gondii tachyzoites by confocal microscopy. The Lac(+) fraction induced hemagglutination (mainly type A human erythrocytes), which was inhibited by beta-galactosides (3 mM lactose and 12 mM galactose) but not by up to 100 mM melibiose (alpha-galactoside), fucose, mannose, or glucose or 0.2 mg/ml heparin. The lectin activity of the Lac(+) preparation was attributed to MIC1, because blotted MIC1, but not native MIC4, bound human erythrocyte type A and fetuin. The copurification of MIC1 and MIC4 may have been due to their association, as reported by others. These data suggest that MIC1 may act through its lectin activity during T. gondii infection.