RESUMO
Despite the efficacy of current immune-chemotherapy for treatment of B-cell non-Hodgkin lymphoma, a substantial proportion of patients relapse, highlighting the need for new therapeutic modalities. The use of live microorganisms to develop anti-tumoural therapies has evolved since Coley's toxin and is now receiving renewed attention. Salmonella Typhimurium has been shown to be highly effective as an anti-tumour agent in many solid cancer models, but it has not been used in haemato-oncology. Here, we report that intra-tumoural administration of LVR01 (attenuated S. Typhimurium strain with safety profile) elicits local and systemic anti-tumour immunity, resulting in extended survival in a lymphoma model. LVR01 induces intra-tumoural recruitment of neutrophils and activated CD8(+) T cells, as well as increasing the natural killer cell activation status. Furthermore, a systemic specific anti-tumour response with a clear T helper type 1 profile was observed. This approach is an alternative therapeutic strategy for lymphoma patients that could be easily moved into clinical trials.
Assuntos
Imunoterapia/métodos , Linfoma de Células B/imunologia , Salmonella typhimurium/imunologia , Animais , Morte Celular/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Epitopos/imunologia , Feminino , Imunidade Humoral , Interferon gama/genética , Interferon gama/metabolismo , Leucócitos/imunologia , Leucócitos/patologia , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Camundongos , Baço/citologia , Baço/imunologia , Baço/microbiologiaRESUMO
Modulation of host responses is an important strategy by which parasites ensure successful establishment and persistence. Host counteraction against this modulation may be required for the host to develop resistance to infection. In this pilot study, experimental infection of dogs with Echinococcus granulosus induced a strong polarization of the cytokine response towards a Th2 phenotype. Consecutive rounds of infection and cure induced resistance to infection resulting in a dramatically lower parasite burden. Repeatedly-infected resistant dogs also lost immune polarization and developed a balanced Th1/Th2 response. No major differences were observed in the production of regulatory cytokines (IL-10, TGF-ß) between dogs with high parasite load and dogs with only few intestinal parasites. These results suggest that E. granulosus-driven immunomodulation contributes to successful infection in the definitive host. This information might be relevant for the development of more effective vaccines against this stage of the parasite.
Assuntos
Citocinas/metabolismo , Equinococose/imunologia , Echinococcus granulosus/imunologia , Animais , Citocinas/classificação , Citocinas/genética , Cães , Equinococose/parasitologia , Nódulos Linfáticos Agregados/imunologia , Projetos Piloto , RNA Mensageiro/metabolismo , Recidiva , Baço/imunologia , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Streptococcus pneumoniae is a major cause of pneumonia in infants and the elderly. Innate defenses are essential to the control of pneumococcal infections, and deficient responses can trigger disease in susceptible individuals. Here we showed that flagellin can locally activate innate immunity and thereby increase the resistance to acute pneumonia. Flagellin mucosal treatment improved S. pneumoniae clearance in the lungs and promoted increased survival of infection. In addition, lung architecture was fully restored after the treatment of infected mice, indicating that flagellin allows the reestablishment of steady-state conditions. Using a flagellin mutant that is unable to signal through Toll-like receptor 5 (TLR5), we established that TLR5 signaling is essential for protection. In the respiratory tract, flagellin induced neutrophil infiltration into airways and upregulated the expression of genes coding for interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), CXCL1, CXCL2, and CCL20. Using depleting antibodies, we demonstrated that neutrophils are major effectors of protection. Further, we found that B- and T-cell-deficient SCID mice clear S. pneumoniae challenge to the same extent as immunocompetent animals, suggesting that these cell populations are not required for flagellin-induced protection. In conclusion, this study emphasizes that mucosal stimulation of innate immunity by a TLR not naturally engaged by S. pneumoniae can increase the potential to cure pneumococcal pneumonia.
Assuntos
Vacinas Bacterianas/imunologia , Flagelina/imunologia , Pneumonia Pneumocócica/prevenção & controle , Streptococcus pneumoniae/imunologia , Administração Intranasal , Animais , Linfócitos B , Vacinas Bacterianas/administração & dosagem , Lavagem Broncoalveolar , Feminino , Flagelina/genética , Imunidade Inata , Pulmão/citologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Mutação , Mucosa Nasal/imunologia , Neutrófilos/fisiologia , Pneumonia Pneumocócica/imunologia , Transdução de Sinais , Streptococcus pneumoniae/genética , Linfócitos T , Receptor 5 Toll-Like/fisiologiaRESUMO
Acute pneumonia caused by Streptococcus pneumoniae is a major cause of child mortality. Antibodies are considered the main effectors of protection in this clinical presentation of pneumococcal invasive disease. To get new insights into the mechanisms involved in the protective immunity, we established a murine experimental model of protection against acute pneumococcal pneumonia and then evaluated the transcriptional, humoral and cellular responses in protected and non-protected animals. We found that intranasal inoculation of a sublethal dose of S. pneumoniae serotype 1 conferred complete protection against a subsequent challenge with a lethal dose of the same strain. Sublethal infection elicited a strong IgM and IgG antibody response against the capsular polysaccharide, as assessed one week later, and an exacerbated influx of neutrophils into the lungs immediately after the lethal challenge. Genome-wide microarray-based transcriptional analysis of whole lungs showed 149 differentially expressed genes among which we found upregulation of Il17a, Ifng and several IL-17A- and IFN-γ-related genes in protected versus non-protected mice. Kinetics analysis showed higher expression levels of Il17a in protected animals at all time points whereas Ifng was upregulated early in the protected mice and later in the non-protected animals. Intracelluar cytokine staining demonstrated that CD4(+) T cells account for a great proportion of the IL-17A produced in the lungs of protected animals. Overall, these results showed that an upregulation of IL-17A- and a timely regulation of IFN-γ-related gene expression, together with development of a Th17 response, are relevant characteristics of the protective immunity against S. pneumoniae acute pneumonia.
Assuntos
Interferon gama/metabolismo , Pulmão/metabolismo , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Células Th17/metabolismo , Animais , Anticorpos Antibacterianos/sangue , Citoproteção/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Neutrófilos/patologia , Polissacarídeos Bacterianos/imunologia , Streptococcus pneumoniae/patogenicidade , Células Th17/imunologia , Células Th17/microbiologia , Células Th17/patologia , Regulação para CimaRESUMO
UNLABELLED: We previously reported that exogenous cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, exerts hepatoprotective effects. Because CT-1 is expressed in the normal liver, we hypothesized that this cytokine may constitute an endogenous defense of the liver against proapoptotic stimuli. Here, we found that CT-1-/- mice died faster than wild-type animals after challenge with a lethal dose of the Fas agonist Jo-2. At sublethal doses of Jo-2, all wild-type mice survived whereas CT-1-/- animals developed extensive hepatocyte apoptosis with 50% mortality at 24 hours. Pretreatment with CT-1 improved survival and reduced injury in both CT-1-/- and wild-type animals. Upon Fas ligation the activation of STAT-3, a molecule that defends the liver against apoptosis, was lower in CT-1-/- mice than in wild-type animals despite similar IL-6 up-regulation in the 2 groups. Analysis of liver transcriptome in CT-1-/- and wild-type mice showed that 9 genes reported to be associated with cell survival/death functions were differentially expressed in the 2 groups. Four of these genes [IGFBP1, peroxiredoxin3, TNFR1, and calpastatin (endogenous inhibitor of calpain)] could be validated by real-time PCR. All of them were down-regulated in CT-1-/- mice and were modulated by CT-1 administration. Treatment of CT-1-/- animals with the calpain inhibitor MDL28170 afforded significant protection against Fas-induced liver injury. CONCLUSION: CT-1-/- mice are highly sensitive to Fas-mediated apoptosis due in part to deficient STAT-3 activation and inadequate control of calpain activity during the apoptotic process. Our data show that CT-1 is a natural defense of the liver against apoptosis. This cytokine may have therapeutic potential.