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1.
Immunology ; 146(3): 486-95, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26302057

RESUMO

Paracoccidioidomycosis is a systemic infection prevalent in Latin American countries. Disease develops after inhalation of Paracoccidioides brasiliensis conidia followed by an improper immune activation by the host leucocytes. Dendritic cells (DCs) are antigen-presenting cells with the unique ability to direct the adaptive immune response by the time of activation of naive T cells. This study was conducted to test whether extracts of P. brasiliensis would induce maturation of DCs. We found that DCs treated with extracts acquired an inflammatory phenotype and upon adoptive transfer conferred protection to infection. Interestingly, interleukin-10 production by CD8(+) T cells was ablated following DC transfer. Further analyses showed that lymphocytes from infected mice were high producers of interleukin-10, with CD8(+) T cells being the main source. Blockage of cross-presentation to CD8(+) T cells by modulated DCs abolished the protective effect of adoptive transfer. Collectively, our data show that adoptive transfer of P. brasiliensis-modulated DCs is an interesting approach for the control of infection in paracoccidioidomycosis.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Interleucina-10/biossíntese , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Paracoccidioidomicose/prevenção & controle , Transferência Adotiva , Animais , Antígenos de Fungos/farmacologia , Diferenciação Celular/imunologia , Apresentação Cruzada , Citocinas/biossíntese , Células Dendríticas/citologia , Células Dendríticas/microbiologia , Feminino , Vacinas Fúngicas/imunologia , Vacinas Fúngicas/farmacologia , Mediadores da Inflamação/metabolismo , Interleucina-10/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
2.
Immunol Cell Biol ; 92(2): 124-32, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24217811

RESUMO

Chloroquine (CQ), an antimalarial drug, has been shown to modulate the immune system and reduce the severity of experimental autoimmune encephalomyelitis (EAE). The mechanisms of disease suppression are dependent on regulatory T cell induction, although Tregs-independent mechanisms exist. We aimed to evaluate whether CQ is capable to modulate bone marrow-derived dendritic cells (DCs) both phenotypically and functionally as well as whether transfer of CQ-modulated DCs reduces EAE course. Our results show that CQ-treated DCs presented altered ultrastructure morphology and lower expression of molecules involved in antigen presentation. Consequently, T cell proliferation was diminished in coculture experiments. When transferred into EAE mice, DC-CQ was able to reduce the clinical manifestation of the disease through the modulation of the immune response against neuroantigens. The data presented herein indicate that chloroquine-mediated modulation of the immune system is achieved by a direct effect on DCs and that DC-CQ adoptive transfer may be a promising approach for avoiding drug toxicity.


Assuntos
Transferência Adotiva , Apresentação de Antígeno/efeitos dos fármacos , Antirreumáticos/farmacologia , Cloroquina/farmacologia , Células Dendríticas , Encefalomielite Autoimune Experimental/terapia , Animais , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/transplante , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos , Linfócitos T/imunologia , Linfócitos T/patologia
3.
PLoS One ; 9(10): e110739, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25329161

RESUMO

The thymus plays an important role shaping the T cell repertoire in the periphery, partly, through the elimination of inflammatory auto-reactive cells. It has been shown that, during Plasmodium berghei infection, the thymus is rendered atrophic by the premature egress of CD4+CD8+ double-positive (DP) T cells to the periphery. To investigate whether autoimmune diseases are affected after Plasmodium berghei NK65 infection, we immunized C57BL/6 mice, which was previously infected with P. berghei NK65 and treated with chloroquine (CQ), with MOG35-55 peptide and the clinical course of Experimental Autoimmune Encephalomyelitis (EAE) was evaluated. Our results showed that NK65+CQ+EAE mice developed a more severe disease than control EAE mice. The same pattern of disease severity was observed in MOG35-55-immunized mice after adoptive transfer of P. berghei-elicited splenic DP-T cells. The higher frequency of IL-17+- and IFN-γ+-producing DP lymphocytes in the Central Nervous System of these mice suggests that immature lymphocytes contribute to disease worsening. To our knowledge, this is the first study to integrate the possible relationship between malaria and multiple sclerosis through the contribution of the thymus. Notwithstanding, further studies must be conducted to assert the relevance of malaria-induced thymic atrophy in the susceptibility and clinical course of other inflammatory autoimmune diseases.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Inflamação/imunologia , Malária/imunologia , Esclerose Múltipla/imunologia , Timo/imunologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Cloroquina/administração & dosagem , Encefalomielite Autoimune Experimental/microbiologia , Inflamação/microbiologia , Interferon gama/biossíntese , Interferon gama/imunologia , Malária/complicações , Malária/microbiologia , Camundongos , Esclerose Múltipla/complicações , Esclerose Múltipla/microbiologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Plasmodium berghei/imunologia , Plasmodium berghei/patogenicidade , Linfócitos T Reguladores/imunologia
4.
PLoS One ; 8(6): e65913, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23799062

RESUMO

BACKGROUND: The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg) cells and suppressive Dendritic Cells (DCs), to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ), an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE), an experimental model for human Multiple Sclerosis, was investigated as well. METHODOLOGY/PRINCIPAL FINDINGS: EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35-55) peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS) and increased frequency of Treg cells. Also, proliferation of MOG35-55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset. CONCLUSION: We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of EAE-inflicted mice, both in prophylactic and therapeutic approaches. We hypothesized that the increased number of regulatory T cells induced by the CQ treatment is involved in the reduction of the clinical signs of EAE.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cloroquina/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Anti-Inflamatórios/farmacologia , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Cloroquina/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Fatores Imunológicos/farmacologia , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/transplante
5.
Photochem Photobiol ; 86(4): 920-4, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20408980

RESUMO

Paracoccidioidomycosis is the most prevalent human mycosis in Latin America. Cutaneous lesions are extremely painful and sensitive, and current treatment with antifungal drugs is lengthy and may cause side effects to patients. In this perspective, the helium-neon (HeNe) laser emerges as a novel therapy form due to its ability to heal wounds without changing cell function. In this work, we evaluate the effects of HeNe laser irradiation on extracellular matrix deposition and expression of cytokines and chemokines in cutaneous lesions caused by experimental infection of Balb/c mice. Our results showed decreased levels of pro-inflammatory interleukin (IL)-17 and tumor necrosis factor-alpha, and of anti-inflammatory IL-10 cytokines in lesions exposed to HeNe laser irradiation. Chemokines CCL3 and CXCL10 showed decreased levels in laser-treated lesions, but no significant difference was observed in relation to CCL5 expression. We also detected decreased density of fibronectin and laminin in HeNe laser-treated lesions. Data presented herein support the validity of our previous results suggesting positive effects of HeNe laser in accelerating wound healing in this experimental model. We believe that HeNe laser is a new nonharmful strategy that may be used as adjuvant and/or alternative therapy for improving treatment of paracoccidioidomycotic lesions.


Assuntos
Quimiocinas/biossíntese , Citocinas/biossíntese , Matriz Extracelular/imunologia , Lasers , Paracoccidioidomicose/imunologia , Paracoccidioidomicose/radioterapia , Animais , Quimiocinas/imunologia , Citocinas/imunologia , Hélio/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neônio/química , Paracoccidioides/imunologia , Paracoccidioides/isolamento & purificação , Paracoccidioides/efeitos da radiação , Paracoccidioidomicose/patologia
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