RESUMO
The feasibility of using oligodeoxynucleotides (ODN) containing unmethylated CpG motifs as parenteral adjuvants for subunit vaccines against RSV was tested in BALB/c mice. Compared with immunization with natural F protein adsorbed to aluminum hydroxide (F/AlOH) adjuvant alone, coadministration of F/AlOH with CpG ODN resulted in statistically significant increases in serum neutralization titers, an enhanced generation of splenic antigen-dependent killer cell precursors, and accelerated clearance of infectious virus from lungs 4 days after challenge. The statistically significant increases in serum IFNgamma and anti-F protein IgG2a titers, and significantly diminished pulmonary IL-5 and eosinophilia after challenge indicated that CpG ODN enhanced the ability of F/AlOH to elicit type 1 immune responses. F protein-specific serum IgE titers were also reduced. Further analysis of pulmonary inflammatory cells demonstrated an expansion of CD8(+) T cells, relative to the CD4(+) T cell compartment. The potency of CpG ODN was not adversely affected in gene knockout mice devoid of the p35 chain of the IL-12 heterodimer. Taken together, the results suggest a novel formulation for naïve recipients of F protein-based subunit vaccines that does not result in a type 2 phenotype.
Assuntos
Adjuvantes Imunológicos , Anticorpos Antivirais/biossíntese , Ilhas de CpG , Pneumonia Viral/prevenção & controle , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sinciciais Respiratórios/imunologia , Vacinação/métodos , Proteínas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Dimerização , Feminino , Imunidade Celular , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Injeções Intramusculares , Interferon gama/biossíntese , Interferon gama/sangue , Interleucina-12/química , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-12/fisiologia , Interleucina-5/biossíntese , Interleucina-5/sangue , Células Matadoras Naturais/imunologia , Pulmão/virologia , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Subunidades Proteicas , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/patologia , Eosinofilia Pulmonar/prevenção & controle , Eosinofilia Pulmonar/virologia , Ratos , Ratos Sprague-Dawley , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sinciciais Respiratórios/isolamento & purificação , Baço/imunologiaRESUMO
A history of acute bronchiolitis in infancy caused by respiratory syncytial virus is a risk factor for recurrent wheezing in early childhood. Because the attachment (G) protein sensitizes mice for pulmonary eosinophilia and because Th2 cells are central in the pathogenesis of asthma, plasma and peripheral blood mononuclear cells (PBMC) from donors with asthma and from healthy donors were evaluated for anti-G protein responses. A significant trend connecting severity of asthma with anti-G protein IgG1 and IgG2 titers was observed. The correlation between anti-F protein IgG3 titers and asthma severity approached significance. Peptide mapping studies revealed that more positive recall responses (interferon-gamma and interleukin-10 secretion) occurred after PBMC from donors with asthma were stimulated with peptides representing the nonglycosylated domain of G protein. The same peptides elicited more positive recall responses (proliferation and interferon-gamma secretion) in the PBMC of healthy donors. These data suggest that a mechanism may exist whereby adaptive immune responses against G protein contribute to wheezing.
