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1.
Nat Med ; 20(6): 633-41, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24743305

RESUMO

Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rß2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rß2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.


Assuntos
Transferência Adotiva/métodos , Doenças Autoimunes/tratamento farmacológico , Linfócitos B Reguladores/metabolismo , Interleucinas/farmacologia , Uveíte/tratamento farmacológico , Animais , Western Blotting , Imunoprecipitação da Cromatina , Primers do DNA/genética , Engenharia Genética , Imunoprecipitação , Interleucina-10/metabolismo , Subunidade beta 2 de Receptor de Interleucina-12/genética , Interleucinas/administração & dosagem , Interleucinas/genética , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas
2.
J Biol Chem ; 287(43): 36012-21, 2012 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-22936807

RESUMO

IL-12 family cytokines are important in host immunity. Whereas some members (IL-12, IL-23) play crucial roles in pathogenesis of organ-specific autoimmune diseases by inducing the differentiation of Th1 and Th17 lymphocytes, others (IL-27 and IL-35) suppress inflammatory responses and limit tissue injury induced by these T cell subsets. In this study, we have genetically engineered a novel IL27p28/IL12p40 heterodimeric cytokine (p28/p40) that antagonizes signaling downstream of the gp130 receptor. We investigated whether p28/p40 can be used to ameliorate uveitis, a CNS inflammatory disease. Experimental autoimmune uveitis (EAU) is the mouse model of human uveitis and is mediated by Th1 and Th17 cells. We show here that p28/p40 suppressed EAU by inhibiting the differentiation and inflammatory responses of Th1 and Th17 cells while promoting expansion of IL-10(+)- and Foxp3(+)-expressing regulatory T cells. Lymph node cells from mice treated with p28/p40 blocked adoptive transfer of EAU to naïve syngeneic mice by immunopathogenic T cells and suppressive effects of p28/p40 derived in part from antagonizing STAT1 and STAT3 pathways induced by IL-27 and IL-6. Interestingly, IL27p28 also suppressed EAU, but to a lesser extent than p28/p40. The inhibition of uveitogenic lymphocyte proliferation and suppression of EAU by p28/p40 and IL27p28 establish efficacy of single chain and heterodimeric IL-12 family cytokines in treatment of a CNS autoimmune disease. Creation of the biologically active p28/p40 heterodimeric cytokine represents an important proof-of-concept experiment, suggesting that cytokines comprising unique IL-12 α- and ß-subunit pairing may exist in nature and may constitute a new class of therapeutic cytokines.


Assuntos
Doenças Autoimunes/imunologia , Subunidade p40 da Interleucina-12/imunologia , Interleucinas/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Uveíte/imunologia , Transferência Adotiva , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Proliferação de Células , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/imunologia , Modelos Animais de Doenças , Humanos , Subunidade p40 da Interleucina-12/genética , Interleucinas/genética , Camundongos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Linfócitos T Reguladores/patologia , Células Th1/patologia , Células Th17/patologia , Uveíte/genética , Uveíte/patologia
3.
Apoptosis ; 17(11): 1144-55, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22911474

RESUMO

Age-related macular degeneration (AMD) is a neurodegenerative disease that causes irreversible central vision loss in the elderly. Retinal pigment epithelium (RPE) has been found to be a key component in AMD pathogenesis. The Ccl2(-/-)/Cx3cr1(-/-) (DKO) mouse on Crb1(rd8) background is created as an AMD model, developing AMD-like retinal lesions. Our study aimed to examine RPE apoptosis in DKO mouse and human ARPE-19 cell line. DKO RPE expressed higher apoptotic proteins when compared with age-matched wild type (WT) RPE in physiological conditions. Apoptosis of primary cultured mouse RPE was evaluated under stimulation with lipopolysaccharide for inflammatory stimulation and 2,3,7,8-tetrachlorodibenzo-p-dioxin or H(2)O(2) for oxidative stress. Compared with WT RPE, DKO RPE was more susceptible to Fas ligand (FasL)-mediated apoptosis under both inflammatory and oxidative stress, with less cell viability and higher expression of apoptotic transcripts and proteins. Decreased cell viability was also observed in ARPE-19 cells under each stimulus. Furthermore, we also investigated the anti-apoptotic effects of decoy receptor 3 (DcR3), a decoy receptor for FasL, on ARPE-19 cells under inflammatory and oxidative stress. DcR3 pre-incubated ARPE-19 cells showed decreased apoptosis, with increased cell viability and decreased expression of apoptotic transcripts and proteins under the stimuli. On the contrary, knockdown of DcR3 in ARPE-19 cells showed totally opposite results. Our study demonstrates that FasL-mediated RPE apoptosis may play a pivotal role in AMD pathogenesis.


Assuntos
Apoptose , Inflamação/patologia , Estresse Oxidativo , Epitélio Pigmentado da Retina/patologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Técnicas de Silenciamento de Genes , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Dibenzodioxinas Policloradas/farmacologia , RNA Interferente Pequeno/metabolismo , Membro 6b de Receptores do Fator de Necrose Tumoral/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo
4.
Biomed Environ Sci ; 24(6): 649-55, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22365401

RESUMO

OBJECTIVE: Although stressful life events represent an etiologic factor of mental health problems in adolescents, few studies have been conducted to address mechanisms linking the stress-psychopathology relation. The present study was designed to examine coping as a mediate factor on the relationship between stressful life events and symptoms of anxiety and depression. METHODS: The participants were 13 512 students from eight cities of China, who participated in a school-based survey. Data were collected by a questionnaire comprising coping, stressful life events, anxiety, and depressive symptoms. As a model, a series of regression equations were used to examine whether coping mediated the association between stressful life events and symptoms of anxiety and depression. RESULTS: Each dimension of stressful life events showed significant correlation with anxiety, depression and coping (all P<0.001). In the model to analyze mediate effects, all standardized coefficients (ß) were significant (all P<0.01), indicating marked mediator effects. Furthermore, negative coping might account for more mediate effects than positive coping on this relationship. CONCLUSION: Coping partially mediated the relationship between stressful life events and mental health during adolescence. This study highlighted an important public health priority for preventive interventions targeting stress-related psychopathology, and for further promoting adolescents' mental health.


Assuntos
Adaptação Psicológica , Ansiedade/psicologia , Depressão/psicologia , Acontecimentos que Mudam a Vida , Saúde Mental , Estudantes/psicologia , Adolescente , China , Interpretação Estatística de Dados , Humanos , Modelos Psicológicos , Inquéritos e Questionários
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 18(3): 766-70, 2010 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-20561447

RESUMO

After treating with chemotherapy or immunosuppressant, malignant diseases of hematopoietic system such as leukemia, malignant lymphoma and aplastic anemia usually induced severe infection such as sepsis. Sepsis which is hard to be diagnosed causes high death rate. This study was purposed to establish an experimental sepsis mouse model so as to provide a basis for pathogenesis and intervention study. A classic caecal ligation and puncture (CLP) was used to establish experimental sepsis model. ELISA was used to detect levels of C5a, IL-6, TNFalpha, and IFN-gamma. Flow Cytometry was applied to measure apoptosis of lymphocytes in thymus and mesentery. The pathologic changes of thymus and spleen were confirmed by HE staining. The results showed that almost 70%-80% mice died at 72 hours after CLP. Only approximate 20% animal survived during finite time, mice in CLP group had significant weight lose. Meanwhile large release of different inflammatory mediators which are related with sepsis (C5a, IL-6, TNF-alpha, and IFN-gamma) was observed after CLP. Apoptosis of lymphocytes in thymus and mesentery lymphonodus was enhanced markedly after CLP. Significantly pathologic injury was also observed in thymus and spleen. It is concluded that a mouse model of experimental sepsis was successfully established by caecal ligation and puncture which can well mimic the clinical symptom of sepsis. The experimental sepsis mouse model provides an excellent tool for exploring the pathogenesis and intervention ways for sepsis accompanied with complicated malignant hematological diseases in vivo.


Assuntos
Modelos Animais de Doenças , Sepse , Animais , Apoptose , Ceco/lesões , Complemento C5a/metabolismo , Interferon gama/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/metabolismo , Sepse/patologia , Baço/patologia , Timo/patologia , Fator de Necrose Tumoral alfa/metabolismo
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 21(1): 24-8, 2005 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-15629077

RESUMO

AIM: To develop rAAV2 containing cDNA of GAD-Ig fusion gene [GAD-Ig fusion gene is constructed by inserting glutamic acid decarboxylase(GAD) into N-terminal of murine IgG3 heavy chain(Ig)], and to study whether rAAV2 mediated GAD-Ig fusion gene expression could induce specific tolerance in IDDM animal model-nonobese diabetic (NOD) mice. METHODS: GAD-Ig cDNA was amplified by PCR from the plasmid BSSK-GAD-Ig and inserted into an eukaryotic expression plasmid pSNAV to construct a recombinant expression plasmid pSNAV/GAD-Ig. Plasmid pSNAV-GAD-Ig was then transfected into the rAAV2 packaging cell-BHK-21 cells using LipofectAMINE TM 2000 to produce rAAV-GAD-Ig. Target gene expression in BHK-21 cells infected by rAAV-GAD-Ig was confirmed by RT-PCR, Western blot and ELISA respectively. Then rAAV-GAD-Ig was injected into intramuscularly NOD mice. Antigen-specific tolerance in NOD mice was detected by specific lymphocytic proliferation reaction to GAD antigen. RESULTS: GAD-Ig gene was inserted into the genome of target cells. Target cells transfected by rAAV2-GAD-Ig could secret GAD-Ig. rAAV2-GAD-Ig induced specific tolerance in NOD mice. CONCLUSION: rAAV2-GAD-Ig was obtained, which can be used in IDDM gene therapy in NOD mice.


Assuntos
DNA Recombinante/genética , Dependovirus/genética , Diabetes Mellitus Tipo 1/terapia , Terapia Genética , Glutamato Descarboxilase/genética , Imunoglobulina G/genética , Cadeias Pesadas de Imunoglobulinas/genética , Animais , Fusão Gênica Artificial , Linhagem Celular , Proliferação de Células , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Expressão Gênica , Vetores Genéticos/genética , Glutamato Descarboxilase/imunologia , Tolerância Imunológica , Imunoglobulina G/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos NOD , Reação em Cadeia da Polimerase , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Cell Mol Immunol ; 2(6): 461-5, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16426497

RESUMO

CD3-specific monoclonal antibody was the first one used for clinical practice in field of transplantation. Recently, renewed interests have elicited in its capacity to prevent autoimmune diabetes by inducing immune tolerance. In this study, we tested whether this antibody can also be used to treat another kind of autoimmune disease myasthenia gravis (MG) and explored the possible mechanisms. MG is caused by an autoimmune damage mediated by antibody- and complement-mediated destruction of AChR at the neuromuscular junction. We found that administration of CD3-specific antibody (Fab)2 to an animal model with experimental autoimmune myasthenia gravis (EAMG) (B6 mice received 3 times of AChR/CFA immunization) could not significantly improve the clinical signs and clinical score. When the possible mechanisms were tested, we found that CD3 antibody treatment slightly down-regulated the T-cell response to AChR, modestly up-regulating the muscle strength. And no significant difference in the titers of IgG2b was found between CD3 antibody treated and control groups. These data indicated that CD3-specific antibody was not suitable for treating MG, an antibody- and complement- mediated autoimmune disease, after this disease has been established. The role of CD3-specific antibody in treating this kind of disease remains to be determined.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Complexo CD3/imunologia , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Miastenia Gravis Autoimune Experimental/imunologia , Animais , Proliferação de Células/efeitos dos fármacos , Eletromiografia , Feminino , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Camundongos , Miastenia Gravis Autoimune Experimental/diagnóstico , Miastenia Gravis Autoimune Experimental/prevenção & controle , Baço/citologia , Baço/efeitos dos fármacos
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