RESUMO
Interleukin-12 (IL-12) is a heterodimeric cytokine that enhances immune responses to bacterial, parasitic, and viral pathogens, and leads to tumor regression in animal models. For this reason, the use of IL-12 as a vaccine adjuvant and as a therapeutic agent for the treatment of cancer is being investigated. Unfortunately, the extreme toxicity of this molecule observed during clinical trials has limited its use. This toxicity correlates with increased IFN-gamma expression, decreased glucose levels, and altered histological responses in the spleen and duodenum. In this study, we show that intranasal (i.n.) delivery of IL-12 is a less toxic route of inoculation compared to the commonly employed subcutaneous route. When delivered i.n., IL-12 induces less systemic IFN-gamma production and fewer pathological tissue changes, yet is efficacious, as indicated by enhanced CD3(+) T cell activation and increased production of Th1-associated immunoglobulins (i.e., serum IgG2a). Thus, IL-12 can be delivered safely and effectively by the i.n. route, a finding which may allow IL-12 to fulfill its clinical potential.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/toxicidade , Interleucina-12/administração & dosagem , Interleucina-12/toxicidade , Administração Intranasal , Animais , Complexo CD3/imunologia , Citocinas/biossíntese , Citocinas/genética , Duodeno/metabolismo , Ensaio de Imunoadsorção Enzimática , Imunoglobulina G/imunologia , Imuno-Histoquímica , Injeções Subcutâneas , Interferon gama/biossíntese , Interferon gama/genética , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C3H , Baço/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Macrolide antibiotics, including azithromycin, have been implicated in the modulation of host immune responses, independently of their antimicrobial properties. The present work was designed to study the effect that azithromycin has on protective humoral immune responses induced by a 7-valent, polysaccharide, pneumococcal conjugate vaccine (PCV7). By use of a murine vaccination/challenge model, it was found that inoculation with azithromycin led to significantly lower primary antibody responses, decreased recall proliferative responses, and, in nasal cavities, impaired clearance of Streptococcus pneumoniae serotype 14 from the nasal cavities. The results demonstrate that azithromycin can be inhibitory with regard to protective immune responsiveness.