RESUMO
BACKGROUND: Allergic asthma is a chronic pulmonary disease characterized by a Th2 inflammatory response. The modulation of a Th2 immune response based on immune deviation to a Th1 pattern or induction and migration of regulatory T cells to the lungs constitutes one of the major therapeutic approaches that is being investigated for the treatment of allergic asthma. The potentials of Mycobacterium leprae 65-kD heat-shock protein or Toll-like receptor 9 ligand (CpG oligodeoxynucleotides) as immune modulators for the treatment of airway allergic disease have been studied individually. OBJECTIVE: Mycobacterial protein combined with CpG was used as immunotherapy for airway allergy. METHODS: Using an ovalbumin-induced asthma model, mice were sensitized and challenged, and then treated with mycobacterial heat-shock protein (Hsp65) combined with CpG. RESULTS: The treatment of mice with established allergy led to the attenuation of eosinophilia, Th2 cytokines and airway hyperresponsiveness. Hsp65 plus CpG treatment also induced an increase in OVA-specific IFN-γ levels and in the frequency of lung inflammatory monocytes. Moreover, we show that the reduction of eosinophilia and the recruitment of inflammatory monocytes to the lungs required early triggering of TLR9, IFN-γ and CCR2 by immunotherapy components. CONCLUSION: In addition to immune deviation to a Th1 response in the modulation of Th2 allergic inflammation, our findings also attribute an important role to the innate response mediated by TLR9, associated with the recruitment of CCR2-dependent monocytes. CLINICAL RELEVANCE: Our findings show that the Hsp65/CpG treatment is a promising strategy for consideration in translational studies.
Assuntos
Asma/tratamento farmacológico , Proteínas de Bactérias/farmacologia , Chaperonina 60/farmacologia , Interferon gama/imunologia , Mycobacterium leprae , Oligodesoxirribonucleotídeos/farmacologia , Receptores CCR2/imunologia , Transdução de Sinais/efeitos dos fármacos , Receptor Toll-Like 9/imunologia , Animais , Asma/genética , Asma/imunologia , Imunoterapia , Interferon gama/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores CCR2/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Receptor Toll-Like 9/genéticaRESUMO
We aimed to evaluate whether the administration of riboflavin to septic animals reduces inflammation, oxidative stress, organ dysfunction, and mortality. C57BL/6 mice, 6-8 weeks old, were allocated to the study group (polymicrobial sepsis induced by cecal ligation and puncture (CLP) + antibiotic + iv riboflavin), control (CLP + antibiotic + iv saline), or naïve (non-operated controls). Serum concentrations of alanine aminotransferase (ALT), creatine kinase-MB (CK-MB), urea, and creatinine, and markers of inflammation [interleukin (IL)-6, tumor necrosis factor (TNF)-α, keratinocyte-derived chemokine (KC), and macrophage inflammatory protein (MIP)-2)], and oxidative stress (malondialdehyde (MDA) were measured 12 h after the experiment. Animal survival rates were calculated after 7 days. Means between groups were compared using linear regression models adjusted under the Bayesian approach. No significant difference was observed between control and study groups in serum concentrations of IL-6 (95% credible interval) (-0.35 to 0.44), TNF-α (-15.7 to 99.1), KC (-0.13 to 0.05), MIP-2 (-0.84 to 0.06), MDA (-1.25 to 2.53), or ALT (-6.6 to 11.5). Serum concentrations of CK-MB (-145.1 to -30.1), urea (-114.7 to -15.1), and creatinine (-1.14 to -0.01) were higher in the study group. Survival was similar in both groups (P=0.8). Therefore, the use of riboflavin in mice undergoing sepsis induced by CLP did not reduce inflammation, oxidative stress, organ dysfunction, or mortality compared with placebo.
Assuntos
Antioxidantes , Sepse , Animais , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Teorema de Bayes , Quimiocinas , Creatinina , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Riboflavina/uso terapêutico , Sepse/tratamento farmacológico , Sepse/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , UreiaRESUMO
Given the impossibility to study the lung immune response during Mycobacterium tuberculosis-latent infection, and consequently, the mechanisms that control the bacterial load, it is reasonable to determine the activation of local immunity in the early phase of the infection. The phosphatidylinositol-3-kinase gamma enzyme (PI3Kγ) is involved in the leukocyte recruitment, phagocytosis and cellular differentiation, and therefore, it is considered a promising target for the development of immunotherapies for chronic inflammatory diseases. Mice genetically deficient in PI3Kγ (PI3Kγ-/-) or WT (Wild Type) were evaluated 15 days post-infection. The enzyme deficiency improved the resistance against infection, increased the frequency of CD4+IL-17+ cells, the production of IL-17 as well as the gene and protein expression of molecules associated with Th17â¯cell differentiation and neutrophil recruitment. Our findings show, for the first time, the participation of the PI3Kγ in vivo in the M. tuberculosis-infection, and suggest an association of Th17â¯cells with protection in the early phase of tuberculosis.
Assuntos
Classe Ib de Fosfatidilinositol 3-Quinase/deficiência , Pulmão/enzimologia , Mycobacterium tuberculosis/patogenicidade , Neutrófilos/enzimologia , Células Th17/enzimologia , Tuberculose Pulmonar/enzimologia , Tuberculose Pulmonar/imunologia , Animais , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Pulmão/imunologia , Pulmão/microbiologia , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Pneumonia/enzimologia , Pneumonia/imunologia , Pneumonia/microbiologia , Transdução de Sinais , Células Th17/imunologia , Células Th17/microbiologia , Fatores de Tempo , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/prevenção & controleRESUMO
The protective effects of mycobacterial infections on lung allergy are well documented. However, the inverse relationship between tuberculosis and type 2 immunity is still elusive. Although type 1 immunity is essential to protection against Mycobacterium tuberculosis it might be also detrimental to the host due to the induction of extensive tissue damage. Here, we determined whether lung type 2 immunity induced by allergen sensitization and challenge could affect the outcome of M. tuberculosis infection. We used two different protocols in which sensitization and allergen challenge were performed before or after M. tuberculosis infection. We found an increased resistance to M. tuberculosis only when allergen exposure was given after, but not before infection. Infected mice exposed to allergen exhibited lower bacterial load and cellular infiltrates in the lungs. Enhanced resistance to infection after allergen challenge was associated with increased gene expression of alternatively activated macrophages (M2 macrophages) and IL-33 levels. Accordingly, either adoptive transfer of M2 macrophages or systemic IL-33 treatment was effective in attenuating M. tuberculosis infection. Notably, the enhanced resistance induced by allergen exposure was dependent on IL-33 receptor ST2. Our work indicates that IL-33 might be an alternative therapeutic treatment for severe tuberculosis.
Assuntos
Interleucina-33/imunologia , Pulmão/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose/imunologia , Alérgenos/imunologia , Alérgenos/toxicidade , Animais , Carga Bacteriana/imunologia , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/genética , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/patologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologiaRESUMO
We aimed to evaluate whether the administration of riboflavin to septic animals reduces inflammation, oxidative stress, organ dysfunction, and mortality. C57BL/6 mice, 6-8 weeks old, were allocated to the study group (polymicrobial sepsis induced by cecal ligation and puncture (CLP) + antibiotic + iv riboflavin), control (CLP + antibiotic + iv saline), or naïve (non-operated controls). Serum concentrations of alanine aminotransferase (ALT), creatine kinase-MB (CK-MB), urea, and creatinine, and markers of inflammation [interleukin (IL)-6, tumor necrosis factor (TNF)-α, keratinocyte-derived chemokine (KC), and macrophage inflammatory protein (MIP)-2)], and oxidative stress (malondialdehyde (MDA) were measured 12 h after the experiment. Animal survival rates were calculated after 7 days. Means between groups were compared using linear regression models adjusted under the Bayesian approach. No significant difference was observed between control and study groups in serum concentrations of IL-6 (95% credible interval) (-0.35 to 0.44), TNF-α (-15.7 to 99.1), KC (-0.13 to 0.05), MIP-2 (-0.84 to 0.06), MDA (-1.25 to 2.53), or ALT (-6.6 to 11.5). Serum concentrations of CK-MB (-145.1 to -30.1), urea (-114.7 to -15.1), and creatinine (-1.14 to -0.01) were higher in the study group. Survival was similar in both groups (P=0.8). Therefore, the use of riboflavin in mice undergoing sepsis induced by CLP did not reduce inflammation, oxidative stress, organ dysfunction, or mortality compared with placebo.