RESUMEN
The antiparasitic activity of 3-hydroxykynurenine (3-HK), one of the major tryptophan catabolites of the kynurenine pathway, against both Trypanosoma cruzi evolutive forms that are important for human infection, trypomastigotes (Tps) and amastigotes (Am), possible targets in the parasite and the drug toxicity to mammalian cells have been investigated. 3-HK showed a potent activity against Am with IC50 values in the micromolar concentration range, while the IC50 values to cause Tps death was â¼6000-times higher, indicating that the replicative form present in the vertebrate hosts is much more susceptible to 3-HK than bloodstream Tps. In addition, 3-HK showed activity against Tps and Am, at concentrations that did not exhibit toxicity to mammalian cells. Ultrastructural analysis and flow cytometry studies indicated that Am and Tps mitochondrion and nuclei contain 3-HK targets. The potency and selectivity of 3-HK, which is generated during T. cruzi infection in human and mice, suggest that 3-HK may be a suitable candidate for drug research and development for Chagas disease.
RESUMEN
PROBLEM: The contribution of Pregnancy-specific glycoproteins (PSG), the major variant of PSG released into the circulation during pregnancy, to the pregnancy-dependent improvement of rheumatoid arthritis (RA) has still not been elucidated. METHOD OF STUDY: Collagen-induced arthritis (CIA) was used to test the hypothesis that PSG1a when released into circulation has a modulatory role on the Th1-pathogenic response, thus improving the CIA symptoms. In vivo expression of PSG1a was induced by injection of the vaccinia (Vac)-based expression vector harboring the complete open-reading frame of PSG1a cDNA. RESULTS: In vivo PSG1a expression during the induction of CIA ameliorated the clinical symptoms, thereby reducing the arthritis score and incidence. Significantly lower levels of IL-17, IL-6, and IFN-γ, but higher levels of TGF-ß and IL-10 were secreted by collagen type II-stimulated spleen mononuclear cells from Vac-PSG1a-treated mice compared with control mice. Moreover, Vac-PSG1a treatment promoted the increase in splenic CD4+CD25+Foxp3+ Treg cells. CONCLUSION: Pre-clinical Vac-PSG1a treatment suppressed the Th1- and Th17-type-specific responses, leading to an increase in splenic Treg cells as well as IL-10- and TGF-ß-secreting cells, with the CIA symptoms being ameliorated.
Asunto(s)
Artritis Experimental/terapia , Inmunomodulación , Glicoproteínas beta 1 Específicas del Embarazo/inmunología , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Antígenos CD4/metabolismo , Células Cultivadas , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Vectores Genéticos/genética , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Glicoproteínas beta 1 Específicas del Embarazo/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Virus VacciniaRESUMEN
Among several explanations for the acceptance of the fetus, the one that suggests that the maternal immune system is suppressed or modified has been the subject of many studies. Thus, it has been proposed that the cells of innate immune system might be able to distinguish the pregnant from the non-pregnant state producing a signal, the so-called signal P. We have previously proposed that pregnancy-specific glycoprotein 1a (PSG1a), a representative member of the main glycoprotein family secreted by placental trophoblast, may modulate the activation of antigen-presenting cells promoting the T-cell shift of the maternal cell immunity toward a less harmful phenotype. In this review, we summarize current knowledge concerning the contribution of pregnancy-specific glycoprotein 1a (PSG1a) to modulate the maternal innate and adaptive immune response in order to assure a successful pregnancy.
Asunto(s)
Inmunidad Adaptativa , Inmunidad Innata , Glicoproteínas beta 1 Específicas del Embarazo/metabolismo , Animales , Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Femenino , Feto/inmunología , Humanos , Activación de Linfocitos , Macrófagos/inmunología , Macrófagos/metabolismo , Placenta/inmunología , Placenta/metabolismo , Embarazo , Trofoblastos/inmunologíaRESUMEN
Because of their plasticity and central role in orchestrating immunity and tolerance, DCs can respond to pregnancy-specific signals, thus promoting the appropriate immune response in order to support pregnancy. Here, we show that pregnancy-specific glycoprotein (PSG1a), the major variant of PSG released into the circulation during pregnancy, targets DCs to differentiate into a subset with a unique phenotype and function. This semi-mature phenotype is able to secrete IL-6 and TGF-ß. PSG1a also affected the maturation of DCs, preventing the up-regulation of some costimulatory molecules, and inducing the secretion of TGF-ß or IL-10 and the expression of programmed death ligand 1 (PD-L1) in response to TLR-9 or CD40 ligation. In addition, PSG1a-treated DCs promoted the enrichment of Th2-type cytokines, IL-17-producing cells, and Treg cells from CD4(+) T cells from DO11.10 Tg mice. Moreover, in vivo expression of PSG1a promoted the expansion of Ag-specific CD4(+) CD25(+) Foxp3(+) Treg cells and IL-17-, IL-4-, IL-5-, and IL-10-secreting cells able to protect against Listeria monocytogenes infection. Taken together, our data indicate that DCs can be targeted by PSG1a to generate the signals necessary to mount an appropriate, well-balanced, and effective immune response able to protect against invading pathogens while at the same time being compatible with a successful pregnancy.
Asunto(s)
Células Dendríticas/inmunología , Proteínas Gestacionales/fisiología , Linfocitos T Reguladores/fisiología , Células Th17/fisiología , Células Th2/fisiología , Animales , Diferenciación Celular , Polaridad Celular , Femenino , Interleucina-17/biosíntesis , Listeriosis/inmunología , Ratones , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: 3-Hydroxy Kynurenine (3-HK) administration during the acute phase of Trypanosoma. cruzi infection decreases the parasitemia of lethally infected mice and improves their survival. However, due to the fact that the treatment with 3-HK is unable to eradicate the parasite, together with the known proapoptotic and immunoregulatory properties of 3-HK and their downstream catabolites, it is possible that the 3-HK treatment is effective during the acute phase of the infection by controlling the parasite replication, but at the same time suppressed the protective T cell response before pathogen clearance worsening the chronic phase of the infection. Therefore, in the present study, we investigated the effect of 3-HK treatment on the development of chronic Chagas' disease. PRINCIPAL FINDINGS: In the present study, we treated mice infected with T. cruzi with 3-HK at day five post infection during 5 consecutive days and investigated the effect of this treatment on the development of chronic Chagas disease. Cardiac functional (electrocardiogram) and histopathological studies were done at 60 dpi. 3-HK treatment markedly reduced the incidence and the severity of the electrocardiogram alterations and the inflammatory infiltrates and fibrosis in heart and skeletal muscle. 3-HK treatment modulated the immune response at the acute phase of the infection impairing the Th1- and Th2-type specific response and inducing TGF-ß-secreting cells promoting the emergence of regulatory T cells and long-term specific IFN-γ secreting cells. 3-HK in vitro induced regulatory phenotype in T cells from T. cruzi acutely infected mice. CONCLUSIONS: Our results show that the early 3-HK treatment was effective in reducing the cardiac lesions as well as altering the pattern of the immune response in experimental Chagas' disease. Thus, we propose 3-HK as a novel therapeutic treatment able to control both the parasite replication and the inflammatory response.
Asunto(s)
Enfermedad de Chagas/prevención & control , Quinurenina/análogos & derivados , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/fisiología , Animales , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Enfermedad Crónica , Femenino , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/parasitología , Interferón gamma/metabolismo , Quinurenina/farmacología , Quinurenina/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Especificidad de la Especie , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/parasitología , Trypanosoma cruzi/inmunología , Trypanosoma cruzi/patogenicidadRESUMEN
Fasciola hepatica is a helminth trematode that migrates through the host tissues until reaching bile ducts where it becomes an adult. During its migration the parasite releases different excretory-secretory products (ESP), which are in contact with the immune system. In this study, we focused on the effect of ESP on the maturation and function of murine bone marrow derived-dendritic cells (DC). We found that the treatment of DC with ESP failed to induce a classical maturation of these cells, since ESP alone did not activate DC to produce any cytokines, although they impaired the ability of DC to be activated by TLR ligands and also their capacity to stimulate an allospecific response. In addition, using an in vitro ovalbumin peptide-restricted priming assay, ESP-treated DC exhibited a capacity to drive Th2 and regulatory T cell (Treg) polarization of CD4(+) cells from DO11.10 transgenic mice. This was characterized by increased IL-4, IL-5, IL-10 and TGF-beta production and the expansion of CD4(+)CD25(+)Foxp3(+) cells. Our results support the hypothesis that ESP from F. hepatica modulate the maturation and function of DC as part of a generalized immunosuppressive mechanism that involves a bias towards a Th2 response and Treg development.