RESUMO
Although several cytokines and chemokines have been investigated as possible mediators of fibrosis in systemic sclerosis (SSc), specific correlation between cytokines and organ involvement have not been found yet, and a cytokine profile characteristic of SSc is far to be identified. We studied the profile of antifibrotic and profibrotic transcripts involved in skin of SSc patients. The mRNA expression was detected by fluorescence-based quantitative real-time PCR (qPCR) in skin's biopsies from 14 patients with SSc and 5 healthy controls. PDGF-A, CTGF, CCL3, IL-6, IL-13, IL-7, IFNγ, IL-17, IL-22 and RORc were analysed in these samples. CCL3, IL-7, IL-13 and IFN-γ were more expressed in skin's biopsy of patients with SSc (P = 0.0002, P = 0.0082, P = 0.0243, P = 0.0335, respectively) when compared with healthy controls. We also found a positive correlation between CCL3 and IL-7 transcripts (P = 0.0050 r = 0.7187). Furthermore, we observed that patients with lung involvement had lower expression of PDGF-A (P = 0.0385). We found an increase in IL-7, IFN-γ, CCL3 and IL-13 relative mRNA expressions on the skin's biopsy of patients with SSc, and a positive correlation between IL-7 and CCL3. These molecules are involved in the pathogenesis of SSc, and how their interactions occur should be the subject of further studies.
Assuntos
Quimiocina CCL3/biossíntese , Interferon gama/biossíntese , Interleucina-13/biossíntese , Interleucina-7/biossíntese , Adulto , Idoso , Biópsia , Quimiocina CCL3/genética , Feminino , Fibrose , Regulação da Expressão Gênica , Humanos , Imunossupressores/uso terapêutico , Interferon gama/genética , Interleucina-13/genética , Interleucina-7/genética , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Derivado de Plaquetas/biossíntese , Fator de Crescimento Derivado de Plaquetas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Transcrição Gênica , Regulação para CimaRESUMO
BACKGROUND: During human pregnancy, infection/inflammation represents an important factor that increases the risk of developing preterm labor. The purpose of this study was to determine if pre-treatment with progesterone has an immunomodulatory effect on human placenta production of endotoxin-induced inflammation and degradation of extracellular matrix markers. METHODS: Placentas were obtained under sterile conditions from pregnancies delivered at term before the onset of labor by cesarean section. Explants from central cotyledons of 10 human placentas were pre-treated with different concentrations of progesterone (0.01, 01, 1.0 µM) and then stimulated with 1000 ng/mL of LPS of Escherichia coli. Cytokines TNFα, IL-1ß, IL-6, IL-8, MIP-1α, IL-10 concentrations in the culture medium were then measured by specific ELISA. Secretion profile of MMP-9 was evaluated by ELISA and zymogram. Statistical differences were determined by one-way ANOVA followed by the appropriate ad hoc test; P < 0.05 was considered statistically significant. RESULTS: In comparison to the explants incubated with vehicle, the LPS treatment led to a significant increase in the level of all cytokines. In comparison to the explants treated only with LPS, pre-treatment with 0.01-1.0 µM progesterone significantly blunted (73, 56, 56, 75, 25, 48 %) the secretion of TNF-α, IL-1ß, IL-6, IL-8, MIP-1α, IL-10, respectively. The MMP-9 induced by LPS treatment was inhibited only with the highest concentration of progesterone. Mifepristone (RU486) blocked the immunosuppressive effect of progesterone. CONCLUSIONS: The present results support the concept that progesterone could be part of the compensatory mechanism that limits the inflammation-induced cytotoxic effects associated with an infection process during gestation.
Assuntos
Endotoxinas/toxicidade , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Placenta/metabolismo , Progesterona/farmacologia , Adulto , Cesárea , Quimiocina CCL3/biossíntese , Feminino , Humanos , Interleucina-10/biossíntese , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Técnicas de Cultura de Órgãos , Placenta/efeitos dos fármacos , Gravidez , Progesterona/fisiologia , Fator de Necrose Tumoral alfa/biossíntese , Adulto JovemRESUMO
Mast cells are crucial elements of the innate immune response. They reside in tissues that are commonly exposed to the external environment, such as the skin and mucosae, where they can rapidly detect the presence of pathogens and mount a potent inflammatory response that recruits other cellular effectors of the immune response. The contribution of mast cells to the immune response to viruses, bacteria, protozoa and multicellular parasites is well established, but there is scarce information about the role of these cells in fungal infections. In this study, we analyzed if mast cells are activated by Candida albicans and if the C-type lectin receptor Dectin-1 is involved in its recognition. We found that both yeasts and hyphae of C. albicans-induced mast cell degranulation and production of TNF-α, IL-6, IL-10, CCL3 and CCL4, while only yeasts were able to induce IL-1ß. Mast cells also produced ROS after stimulation with both dimorphic phases of C. albicans. When mast cells were activated with yeasts and hyphae, they showed decreased expression of IκBα and increased presence of phosphorylated Syk. Blockade of the receptor Dectin-1, but not Toll-like receptor 2, decreased TNF-α production by mast cell in response to C. albicans. These results indicate that mast cells are capable of sensing the two phases of C. albicans, and suggest that mast cells participate as an early inductor of inflammation during the early innate immune response to this fungus.
Assuntos
Candida albicans/imunologia , Degranulação Celular/imunologia , Inflamação/imunologia , Lectinas Tipo C/imunologia , Mastócitos/imunologia , Animais , Células Cultivadas , Quimiocina CCL3/biossíntese , Quimiocina CCL4/biossíntese , Hifas/imunologia , Quinase I-kappa B/metabolismo , Interleucina-10/biossíntese , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Fosforilação/imunologia , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Quinase Syk , Fator de Necrose Tumoral alfa/biossíntese , Leveduras/imunologiaRESUMO
The recent increase in immigration of people from areas endemic for Chagas disease (Trypanosoma cruzi) to the United States and Europe has raised concerns about the transmission via blood transfusion and organ transplants in these countries. Infection by these pathways occurs through blood trypomastigotes (BT), and these forms of T. cruzi are completely distinct of metacyclic trypomastigotes (MT), released by triatomine vector, in relation to parasite-host interaction. Thus, research comparing infection with these different infective forms is important for explaining the potential impacts on the disease course. Here, we investigated tissue parasitism and relative mRNA expression of cytokines, chemokines, and chemokine receptors in the heart during acute infection by MT or BT forms in dogs. BT-infected dogs presented a higher cardiac parasitism, increased relative mRNA expression of pro-inflammatory and immunomodulatory cytokines and of the chemokines CCL3/MIP-1α, CCL5/RANTES, and the chemokine receptor CCR5 during the acute phase of infection, as compared to MT-infected dogs. These results suggest that infection with BT forms may lead to an increased immune response, as revealed by the cytokines ratio, but this kind of immune response was not able to control the cardiac parasitism. Infection with the MT form presented an increase in the relative mRNA expression of IL-12p40 as compared to that of IL-10 or TGF-ß1. Correlation analysis showed increased relative mRNA expression of IFN-γ as well as IL-10, which may be an immunomodulatory response, as well as an increase in the correlation of CCL5/RANTES and its CCR5 receptor. Our findings revealed a difference between inoculum sources of T. cruzi, as vectorial or transfusional routes of T. cruzi infection may trigger distinct parasite-host interactions during the acute phase, which may influence immunopathological aspects of Chagas disease.
Assuntos
Doença de Chagas/imunologia , Citocinas/genética , Coração/parasitologia , Miocárdio/imunologia , Trypanosoma cruzi/imunologia , Animais , Doença de Chagas/parasitologia , Quimiocina CCL3/biossíntese , Quimiocina CCL3/genética , Quimiocina CCL5/biossíntese , Quimiocina CCL5/genética , Modelos Animais de Doenças , Cães , Feminino , Interações Hospedeiro-Parasita/imunologia , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-10/biossíntese , Interleucina-10/genética , Subunidade p40 da Interleucina-12/biossíntese , Subunidade p40 da Interleucina-12/genética , Masculino , Miocárdio/metabolismo , RNA Mensageiro/biossíntese , Receptores CCR5/biossíntese , Receptores CCR5/genética , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genéticaRESUMO
OBJECTIVE: The aim of this study was to compare the production of the chemokines CCL3 and CXCL12 by cultured dental pulp fibroblasts from permanent (PDPF) and deciduous (DDPF) teeth under stimulation by Porphyromonas gingivalis LPS (PgLPS). MATERIAL AND METHODS: Primary culture of fibroblasts from permanent (n=3) and deciduous (n=2) teeth were established using an explant technique. After the fourth passage, fibroblasts were stimulated by increasing concentrations of PgLPS (0-10 µg/mL) at 1, 6 and 24 h. The cells were tested for viability through MTT assay, and production of the chemokines CCL3 and CXCL12 was determined through ELISA. Comparisons among samples were performed using One-way ANOVA for MTT assay and Two-way ANOVA for ELISA results. RESULTS: Cell viability was not affected by the antigen after 24 h of stimulation. PgLPS induced the production of CCL3 by dental pulp fibroblasts at similar levels for both permanent and deciduous pulp fibroblasts. Production of CXCL12, however, was significantly higher for PDPF than DDPF at 1 and 6 h. PgLPS, in turn, downregulated the production of CXCL12 by PDPF but not by DDPF. CONCLUSION: These data suggest that dental pulp fibroblasts from permanent and deciduous teeth may present a differential behavior under PgLPS stimulation.
Assuntos
Quimiocina CCL3/biossíntese , Quimiocina CXCL12/biossíntese , Polpa Dentária/metabolismo , Fibroblastos/metabolismo , Porphyromonas gingivalis/metabolismo , Análise de Variância , Sobrevivência Celular , Células Cultivadas , Polpa Dentária/citologia , Dentição Permanente , Ensaio de Imunoadsorção Enzimática , Fibroblastos/citologia , Humanos , Técnicas In Vitro , Fatores de Tempo , Dente Decíduo/metabolismoRESUMO
Rheumatic fever (RF) is an autoimmune disease triggered by Streptococcus pyogenes infection frequently observed in infants from developing countries. Rheumatic heart disease (RHD), the major sequel of RF, leads to chronic inflammation of the myocardium and valvular tissue. T cells are the main population infiltrating cardiac lesions; however, the chemokines that orchestrate their recruitment are not clearly defined. Here, we investigated the expression of chemokines and chemokine receptors in cardiac tissue biopsies obtained from chronic RHD patients. Our results showed that CCL3/MIP1α gene expression was upregulated in myocardium while CCL1/I-309 and CXCL9/Mig were highly expressed in valvular tissue. Auto-reactive T cells that infiltrate valvular lesions presented a memory phenotype (CD4(+)CD45RO(+)) and migrate mainly toward CXCL9/Mig gradient. Collectively, our results show that a diverse milieu of chemokines is expressed in myocardium and valvular tissue lesions and emphasize the role of CXCL9/Mig in mediating T cell recruitment to the site of inflammation in the heart.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Quimiocina CXCL9/metabolismo , Valvas Cardíacas/imunologia , Miocárdio/imunologia , Cardiopatia Reumática/imunologia , Adolescente , Adulto , Movimento Celular/imunologia , Quimiocina CCL1/biossíntese , Quimiocina CCL1/imunologia , Quimiocina CCL3/biossíntese , Quimiocina CCL3/imunologia , Quimiocina CXCL9/biossíntese , Criança , Pré-Escolar , Feminino , Fibrose , Valvas Cardíacas/metabolismo , Humanos , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Neovascularização Patológica/imunologia , Febre Reumática/imunologia , Febre Reumática/microbiologia , Streptococcus pyogenes , Adulto JovemRESUMO
PURPOSE: In spite of the recent advances in surgery and antitumor drugs, the brain tumors, like glioblastoma, have shown a poor prognosis. The aim of this study was to determine the effect of pertussis toxin (PTx) as immunomodulatory molecule on glial tumors induced by C6 glioma cells. METHODS: Given the pleiotropic effect of PTx on the immune system, we analyzed the effect of PTx on CD4+/CD25+/FoxP3+ (Treg) cells like as immunotherapeutic adjuvant. Thirty rats with a glial tumor of 1.5 cm in diameter were separated in two groups: the first group was treated with PTx and the second group was non-treated (controls). Tumoral volume was measured weekly; tumor, blood and spleen were taken for analysis of subpopulations of T cells, apoptotic index and cytokine contents, in both groups. RESULTS: We observed a significant decrease in tumor volume in the PTx group; this was associated with a decreased in the number of Treg cells, in both spleen and tumor. The percentage of apoptotic cells was increased as compared with that of controls. The production of proinflammatory cytokines was increased in mRNA for IL-6 as well as a small increase in the mRNA expression of perforin and granzime in tumors from rats treated with PTx. No changes were found in the mRNA expression of MCP-1 and MIP-1α. CONCLUSION: These results suggest that PTx could be an immunotherapeutic adjuvant in the integral therapy against glial tumors.
Assuntos
Glioma/tratamento farmacológico , Fatores Imunológicos/farmacologia , Toxina Pertussis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Quimiocina CCL3/biossíntese , Quimiocina CCL3/genética , Quimiocina CCL3/imunologia , Feminino , Glioma/imunologia , Glioma/patologia , Granzimas/biossíntese , Granzimas/genética , Granzimas/imunologia , Fatores Imunológicos/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-6/biossíntese , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Perforina/biossíntese , Perforina/genética , Perforina/imunologia , Toxina Pertussis/imunologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologiaRESUMO
Immunological dysfunction has been described to occur in chronic idiopathic urticaria (CIU), most notably in association with an inflammatory process. Some pharmacological agents as statins--drugs used in hypercholesterolaemia--display a broad effect on the immune response and thus should be tested in vitro in CIU. Our main objectives were to evaluate the effects of statins on the innate and adaptive immune response in CIU. Simvastatin or lovastatin have markedly inhibited the peripheral blood mononuclear cells (PBMC) proliferative response induced by T and B cell mitogens, superantigen or recall antigen. Simvastatin arrested phytohaemaglutinin (PHA)-induced T cells at the G0/G1 phase, inhibiting T helper type 1 (Th1), Th2, interleukin (IL)-10 and IL-17A cytokine secretion in both patients and healthy control groups. Up-regulation of suppressor of cytokine signalling 3 (SOCS3) mRNA expression in PHA-stimulated PBMCs from CIU patients was not modified by simvastatin, in contrast to the enhancing effect in the control group. Statin exhibited a less efficient inhibition effect on cytokine production [IL-6 and macrophage inflammatory protein (MIP)-1α] induced by Toll-like receptor (TLR)-4, to which a statin preincubation step was required. Furthermore, statin did not affect the tumour necrosis factor (TNF)-α secretion by lipopolysaccharide (LPS)-stimulated PBMC or CD14+ cells in CIU patients. In addition, LPS-activated PBMC from CIU patients showed impaired indoleamine 2,3-dioxygenase (IDO) mRNA expression compared to healthy control, which remained at decreased levels with statin treatment. Statins exhibited a marked down-regulatory effect in T cell functions, but were not able to control TLR-4 activation in CIU patients. The unbalanced regulatory SOCS3 and IDO expressions in CIU may contribute to the pathogenesis of the disease.
Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Lovastatina/farmacologia , Sinvastatina/farmacologia , Urticária/imunologia , Adulto , Idoso , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL3/biossíntese , Doença Crônica , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Interleucina-10/biossíntese , Interleucina-10/metabolismo , Interleucina-17/biossíntese , Interleucina-17/metabolismo , Interleucina-6/biossíntese , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , RNA Mensageiro/biossíntese , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Proteínas Supressoras da Sinalização de Citocina/genética , Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Urticária/tratamento farmacológico , Adulto JovemRESUMO
INTRODUCTION: Fibroblasts are the most abundant cells in dental pulp. To investigate their capacity to produce the chemokines CCL3, CXCL8, and CXCL12 as well as nitric oxide (NO), we evaluated the production of these mediators in supernatants of cultured human dental pulp fibroblasts (HDPF) stimulated by heat-killed Enterococcus faecalis (HKEF). METHODS: Primary cultures of HDPF were stimulated with medium alone or HKEF (1:1, 10:1, or 100:1 bacteria:fibroblast) for 1, 6, and 24 hours. Chemokines and NO were assessed through enzyme-linked immunosorbent assay and Griess reaction, respectively. Statistical analysis was performed by using analysis of variance and Tukey post test. RESULTS: CCL3 was not detected, whereas constitutive CXCL8 was not affected. Production of CXCL12 was increased at 1 and 6 hours, and NO was increased at the concentration of 1:1 bacteria:fibroblast at 24 hours. Viability and proliferation assays did not reveal cell number differences. CONCLUSIONS: These findings demonstrate that heat-killed E. faecalis is able to increase production of CXCL12 and NO by HDPF.
Assuntos
Quimiocina CXCL12/biossíntese , Polpa Dentária/imunologia , Polpa Dentária/microbiologia , Enterococcus faecalis/química , Óxido Nítrico/biossíntese , Proliferação de Células , Parede Celular/química , Células Cultivadas , Quimiocina CCL3/biossíntese , Meios de Cultivo Condicionados , Polpa Dentária/citologia , Polpa Dentária/metabolismo , Enterococcus faecalis/imunologia , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/microbiologia , Temperatura Alta , Humanos , Interleucina-8/biossíntese , Regulação para Cima , Fatores de VirulênciaRESUMO
INTRODUCTION: Periapical chronic lesion formation involves activation of the immune response and alveolar bone resorption around the tooth apex. However, the overall roles of T helper type 1 (Th1), Th2, and T-regulatory cell (Treg) responses and osteoclast regulatory factors in periapical cysts and granulomas have not been fully determined. This study aimed to investigate whether different forms of apical periodontitis, namely cysts and granulomas, show different balances of Th1, Th2 regulators, Treg markers, and factors involved in osteoclast chemotaxis and activation. METHODS: Gene expression of these factors was assessed using quantitative real-time polymerase chain reaction, in samples obtained from healthy gingiva (n = 8), periapical granulomas (n = 20), and cysts (n = 10). RESULTS: Periapical cysts exhibited a greater expression of GATA-3, while a greater expression of T-bet, Foxp3, and interleukin-10 (IL-10) was seen in granulomas. The expression of interferon-gamma, IL-4, and transforming growth factor-beta was similar in both lesions. Regarding osteoclastic factors, while the expression of SDF-1alpha/CXCL12 and CCR1 was higher in cysts, the expression of RANKL was significantly higher in granulomas. Both lesions exhibited similar expression of CXCR4, CKbeta8/CCL23, and osteoprotegerin, which were significantly higher than in control. CONCLUSION: Our results showed a predominance of osteoclast activity in granulomas that was correlated with the Th1 response. The concomitant expression of Treg cell markers suggests a possible suppression of the Th1 response in granulomas. On the other hand, in cysts the Th2 activity is augmented. The mechanisms of periradicular lesion development are still not fully understood but the imbalance of immune and osteoclastic cell activity in cysts and granulomas seems to be critically regulated by Treg cells.
Assuntos
Osteoclastos/fisiologia , Granuloma Periapical/imunologia , Cisto Radicular/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Perda do Osso Alveolar/imunologia , Perda do Osso Alveolar/metabolismo , Quimiocina CCL3/biossíntese , Quimiocina CXCL12/biossíntese , Quimiocinas CC/biossíntese , Quimiotaxia , Doença Crônica , Fatores de Transcrição Forkhead/biossíntese , Fator de Transcrição GATA3/biossíntese , Expressão Gênica , Humanos , Interferon gama/biossíntese , Interleucina-10/biossíntese , Pessoa de Meia-Idade , Osteoprotegerina/biossíntese , Granuloma Periapical/metabolismo , Ligante RANK/biossíntese , Cisto Radicular/metabolismo , Receptores CCR1/biossíntese , Receptores CXCR4/biossíntese , Proteínas com Domínio T/biossínteseRESUMO
The regulatory effect of mast cells on the pathogenesis of leishmaniasis is unclear. We report a comparative analysis of TLR2 membrane expression, TNF-α, IL-10 and MIP-1α production, and granule release of bone marrow-derived mast cells (BMMCs) from susceptible BALB/c and resistant C57BL/6 mice, stimulated in vitro with Leishmania mexicana lipophosphoglycan (LPG). We studied the kinetics of mast cell degranulation and parasite numbers in lesions of both mouse strains infected with L. mexicana. We found that BMMCs of C57BL/6 mice expressed more TLR2 and produced higher levels of both cytokines and MIP-1α, whereas BALB/c BMMCs significantly augmented their granule release. Lesions of BALB/c mice showed higher levels of degranulated mast cells at 3 h of infection, whereas after 3 days of infection, the number of degranulated mast cells in C57BL/6 was higher than in BALB/c lesions. Throughout infection, BALB/c mice harboured more parasites. The regulatory effect of mast cells seems to depend on the genetic background of the host: mast cells of BALB/c mice facilitate disease progression due to an augmented inflammatory response early in the infection, whereas mast cells of C57BL/6 mice produce cytokines that regulate inflammation and maintain an elevated number of immune cells in the lesions, promoting disease control.
Assuntos
Glicoesfingolipídeos/imunologia , Leishmania mexicana/imunologia , Leishmania mexicana/patogenicidade , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/imunologia , Mastócitos/imunologia , Animais , Contagem de Células , Degranulação Celular , Quimiocina CCL3/biossíntese , Modelos Animais de Doenças , Interleucina-10/biossíntese , Leishmaniose Cutânea/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Doenças dos Roedores/genética , Doenças dos Roedores/imunologia , Doenças dos Roedores/patologia , Pele/parasitologia , Pele/patologia , Receptor 2 Toll-Like/biossíntese , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Experimental models of infection with Leishmania spp. have provided knowledge of several immunological events involved in the resistance mechanism used by the host to restrain parasite growth. It is well accepted that concomitant immunity exists, and there is some evidence that it would play a major role in long-lasting acquired resistance to infection. In this paper, the resistance to Leishmania amazonensis infection in C57BL/6 mice infected with Leishmania major was investigated. C57BL/6 mice, which spontaneously heal lesions caused by infection with L. major, were infected with L. amazonensis at different times before and after L. major. We demonstrated that C57BL/6 mice previously infected with L. major restrain pathogenic responses induced by L. amazonensis infection and decrease parasite burdens by one order of magnitude. Co-infected mice showed production of IFN-gamma in lesions similar to mice infected solely with L. major, but higher TNF-alpha and nitric oxide synthase (iNOS) mRNA expression was observed. Surprisingly, the restrained pathogenic response was not related to IL-10 production, as evidenced by lower levels of both mRNA, protein expression in lesions from co-infected mice and in co-infections in IL-10(-/-) mice. Examination of the inflammatory infiltrate at the site of infection showed a reduced number of monocytes and lymphocytes in L. amazonensis lesions. Additionally, differential production of the CCL3/MIP-1 alpha and CCL5/RANTES was observed. We suggest that the control of lesion progression caused by L. amazonensis in C57BL/6 mice pre-infected with L. major is related to the induction of a down-regulatory environment at the site of infection with L. amazonensis.
Assuntos
Leishmania major/imunologia , Leishmania/imunologia , Leishmaniose/imunologia , Animais , Quimiocina CCL3/biossíntese , Quimiocina CCL5/biossíntese , Feminino , Pé/patologia , Interferon gama/biossíntese , Interleucina-10/deficiência , Interleucina-10/imunologia , Leishmaniose/parasitologia , Leishmaniose/patologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Óxido Nítrico Sintase/biossíntese , Fator de Necrose Tumoral alfa/biossínteseRESUMO
BACKGROUND: Certain CC chemokines including ligands for the HIV-1 coreceptor CCR5 are associated with suppression of HIV-1 infection. Whether the release of these chemokines from lymphocytes influences treatment outcome in children receiving antiretroviral therapy is not known. METHODS: A study of 175 HIV-infected children in Rio de Janeiro, Brazil was conducted to compare clinical measures and HIV-suppressive chemokine release. Clinical measures including %CD4 T cells, viral loads, and antiretroviral drug-resistant mutations were obtained. Chemokine release was measured in cultures of peripheral blood mononuclear cells collected from 135 children before or after receiving therapy. Chemokine levels were compared between subject groups stratified according to clinical measures and treatment regimen (1-2, 3-4, or no antiretrovirals) extant at the time of cell sample collection. RESULTS: Mean viral loads did not vary significantly between treatment groups although there were significant differences in %CD4 T cells. Virus from children taking 3-4 antiretrovirals had significantly more drug-resistant mutations than did virus from those receiving 1-2 drugs. Among antiretroviral-treated children, there was a significant direct relationship between %CD4 T cells and MIP-1alpha/CCL3 and macrophage-derived chemokine/CCL22 production. In addition, there was a significant inverse relationship between viral load and MIP-1alpha production in patients receiving 3-4 antiretrovirals. Greater recovery of %CD4 T cells after therapy was associated with higher MIP-1alpha and macrophage-derived chemokine production at baseline. CONCLUSIONS: The production of HIV-suppressive chemokines is associated with better outcome in children receiving antiretroviral regimens in settings where drug-resistant mutations are prevalent. Such information may provide insights for the design of treatment strategies for pediatric HIV infection under similar circumstances.