RESUMO
Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases, such as rheumatoid arthritis (RA). Here, we characterize monocyte-derived TolDCs from RA patients modulated with dexamethasone and activated with monophosphoryl lipid A (MPLA), referred to as MPLA-tDCs, in terms of gene expression, phenotype, cytokine profile, migratory properties, and T cell-stimulatory capacity in order to explore their suitability for cellular therapy. MPLA-tDCs derived from RA patients displayed an anti-inflammatory profile with reduced expression of co-stimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating toward the lymphoid chemokines CXCL12 and CCL19. These MPLA-tDCs induced hyporesponsiveness of autologous CD4+ T cells specific for synovial antigens in vitro. Global transcriptome analysis confirmed a unique transcriptional profile of MPLA-tDCs and revealed that RA-associated genes, which were upregulated in untreated DCs from RA patients, returned to expression levels of healthy donor-derived DCs after treatment with dexamethasone and MPLA. Thus, monocyte-derived DCs from RA patients have the capacity to develop tolerogenic features at transcriptional as well as at translational level, when modulated with dexamethasone and MPLA, overcoming disease-related effects. Furthermore, the ability of MPLA-tDCs to impair T cell responses to synovial antigens validates their potential as cellular treatment for RA.
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PURPOSE: To study the efficacy and incidence of treatment-related side effects of mycophenolate mofetil (MMF) therapy in patients with noninfectious inflammatory eye diseases. METHODS: Retrospective cohort study of 27 Chilean patients treated for noninfectious inflammatory eye diseases using MMF therapy over a 10-year period. Main outcome measures were: ability to control ocular inflammation and to taper prednisone to ≤10 mg daily (treatment success); incidence of treatment-related side effects. RESULTS: The proportion of patients with sustained control of inflammation was 81.48% at 6 months. Additionally 55.56% and 22.22% of patients succeeded in tapering their prednisone to 5-10 mg/day and <5 mg/day, at 6 months. Two patients developed a neoplasia during MMF therapy; however, this cohort is too small to interpret the significance of this relation to MMF treatment. CONCLUSIONS: MMF seems to be an effective corticosteroid-sparing agent with an acceptable safety profile.
Assuntos
Imunossupressores/uso terapêutico , Inflamação/tratamento farmacológico , Ceratite/tratamento farmacológico , Ácido Micofenólico/análogos & derivados , Esclerite/tratamento farmacológico , Uveíte/tratamento farmacológico , Adulto , Chile , Estudos de Coortes , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Inflamação/diagnóstico , Ceratite/diagnóstico , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Estudos Retrospectivos , Esclerite/diagnóstico , Resultado do Tratamento , Uveíte/diagnósticoRESUMO
A woman with severe and longstanding systemic lupus erythematosus presented with a 1-week history of fever up to 38°C and pain in her right flank. Computed tomography scan of the chest revealed interstitial infiltrates and multiple nodules. Bronchoalveolar lavage did not show any inflammatory cells. Gram stain and cultures for aerobic and anaerobic bacteria, fungi, and Nocardia; acid-fast staining; polymerase chain reaction for tuberculosis, cytomegalovirus, herpesvirus 6, and parvovirus B19; and IF staining for pneumocystic and Legionella antigen were all negative. Transbronchial biopsy was nondiagnostic. Open lung biopsy with polymerase chain reaction and immunohistochemistry analyses revealed herpes simplex virus 1 infection. Acyclovir therapy was initiated and was followed by significant improvement. Herpes simplex virus 1 infection (although unusual) should be considered in patients with systemic lupus erythematosus with an atypical clinical presentation.
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Herpes Simples/diagnóstico , Herpes Simples/etiologia , Herpesvirus Humano 1 , Lúpus Eritematoso Sistêmico/complicações , Pneumonia/diagnóstico , Pneumonia/virologia , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Biópsia , Feminino , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/isolamento & purificação , Humanos , Pulmão/patologia , Pulmão/virologia , Pessoa de Meia-Idade , Pneumonia/tratamento farmacológico , Resultado do TratamentoRESUMO
Citrullinated vimentin (cVIM) is one of the antigens specifically targeted by anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients. The association between ACPA and certain HLA-DRB1 alleles, those coding for the shared epitope (SE), suggests that this response could be T-cell mediated. HLA-DR9 alleles, which do not code for the SE, have recently been associated with ACPA (+) RA. The objective of this work was to study CD4+ T cell responses to cVIM in RA patients and healthy controls carrying HLA-DR9 alleles. Fourteen RA patients and ten healthy controls previously genotyped for HLA-DRB1 were studied for the presence of serum anti-cVIM antibodies by Western blot and ELISA. Peripheral blood mononuclear cells were stimulated with native vimentin and cVIM, and CD4+ T cells proliferation was assessed by flow cytometry. Citrulline-specific CD4+ T cells proliferation was found not only in RA patients but also in healthy controls. Although most patients carrying HLA-DR9 alleles present anti-cVIM antibodies, HLA-DR9 alleles were associated with weaker cVIM-driven CD4+ T-cell responses among RA patients. These results suggest that HLA-DR9 alleles could exert a protective effect on the recognition of cVIM epitopes by CD4+ T cells. In this context, other citrullinated proteins may break T and B cell tolerance, with cVIM only acting as a cross-reactive target for ACPA.
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Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/imunologia , Citrulina/imunologia , Subtipos Sorológicos de HLA-DR/genética , Vimentina/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Western Blotting , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Chile , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Genótipo , Humanos , Epitopos Imunodominantes , Ativação Linfocitária , Pessoa de Meia-Idade , FenótipoRESUMO
The aim of this work was to study the effect of anti-TNF treatment on CD4+ Th1, Th17 and regulatory T cells (Tregs), together with CD8+ T cells and NK cells from rheumatoid arthritis (RA) patients. For this purpose, 18 RA patients received adalimumab during 16weeks and their peripheral blood lymphocytes were assessed by flow cytometry at the beginning and at the end of the study. We found that the proportion of Th17 cells was directly correlated with Th1 cells, but inversely correlated with IFN-γ-producing NK cells. A decrease was observed in Th1, Th17 cells and IFN-γ-producing CD8+ T cells by anti-TNF therapy. Conversely, the proportion of Tregs increased, as did the percentage of IFN-γ-producing NK cells. We postulate that a rise in IFN-γ production due to recovery of NK cells' function, together with expanded Tregs, contribute to decrease the Th17 response in anti-TNF-treated RA patients.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Imunoterapia , Fator de Necrose Tumoral alfa/imunologia , Adalimumab , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Contagem de Células , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologiaRESUMO
The introduction of antitumor necrosis factor (TNF) agents has improved the outcome for many patients with rheumatoid arthritis (RA). To date, the only replicated genetic predictor of anti-TNF response is the -308 G > A single-nucleotide polymorphism in the TNF promoter region. The presence of the -308 TNF G/G genotype appears to be a marker of good response to anti-TNF treatment. Anti-citrullinated protein antibodies (ACPA) have been linked with erosive disease, and have been established as the single most reliable prognostic factor in clinical practice. To test the hypothesis that the ACPA status may affect the -308 G/G patients rate of response to TNF blockade, we prospectively investigated a group of 52 RA patients with the -308 G/G genotype who were ACPA (+) or ACPA (-). All patients were treated with adalimumab, and the clinical response was studied using the Disease Activity Score in 28 joints (DAS28) at 24 weeks of treatment. Over 85% of patients were DAS28 responders in both groups. No significant differences were found between patients from both groups, according to the DAS28 criteria of response at week 24 (p = 0.79). In conclusion, our findings suggest that the ACPA status does not affect the clinical response to anti-TNF therapy in -308 TNF G/G patients.
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Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide , Autoanticorpos/sangue , Peptídeos Cíclicos/sangue , Polimorfismo Genético , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/genética , Adalimumab , Adulto , Anticorpos Monoclonais Humanizados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
PURPOSE: To prospectively compare 2 immunosupressive regimens in patients with active Vogt-Koyanagi-Harada disease in spite of systemic glucocorticoid treatment. METHODS: Forty-four patients were diagnosed between 1998 and 2005. Twenty-one developed chronic intraocular inflammation in spite of glucocorticoid treatment and were randomized to receive either prednisone and azathioprine (AZA) (n = 12) or prednisone and cyclosporine (CyA) (n = 9). RESULTS: In the AZA group Tyndall score decreased from 1.21 +/- 1.10 to 0.29 +/- 0.62 (p < .01), and visual acuity (LogMAR) improved from 0.32 +/- 0.35 to 0.09 +/- 0.16 (p < .001). In the CyA group Tyndall score decreased from 1.67 +/- 1.08 to 0.16 +/- 0.51 (p < .001), and visual acuity improved from 0.41 +/- 0.40 to 0.25 +/- 0.42 (p < .001). Patients in the AZA group needed a significantly higher average prednisone dose and total cumulative dose than those in the CyA group, p < .01 for each comparison. CONCLUSIONS: Both regimens showed a good clinical efficacy, but CyA seems to be a better glucocorticoid-sparing agent than AZA.
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Azatioprina/administração & dosagem , Ciclosporina/administração & dosagem , Glucocorticoides/administração & dosagem , Terapia de Imunossupressão/métodos , Imunossupressores/administração & dosagem , Prednisona/administração & dosagem , Síndrome Uveomeningoencefálica/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Acuidade Visual , Adulto JovemRESUMO
INTRODUCTION: Several molecules help preserve peripheral B cell tolerance, but when altered, they may predispose to autoimmunity. This work studied the expression of the costimulatory molecule CD86 and the inhibitory receptor for IgG immune complexes FcgammaRIIb (CD32b), on B cells from rheumatoid arthritis (RA) patients, and the influence of anti-tumor necrosis factor (TNF) therapy. METHODS: Peripheral B cells from 18 RA patients and 13 healthy donors were characterized using flow cytometry. Eleven patients who underwent a six-month adalimumab therapy were further assessed for phenotypic changes on their B cells. RESULTS: RA patients exhibited a high percentage of naïve and memory B cells expressing CD86. In contrast, expression of FcgammaRIIb was significantly reduced on RA memory B cells and plasmablasts as compared to healthy donors, probably due to downregulation of this receptor when differentiating from naïve to memory cells. These alterations on FcgammaRIIb were associated with high levels of anti-citrullinated vimentin autoantibodies. In addition, treatment with adalimumab normalized the expression of CD86 on memory B cells and reduced the expression of FcgammaRIIb, mainly on naïve B cells. CONCLUSIONS: Our findings show that peripheral B cells from RA patients have an altered expression of key molecules, such as CD86 and FcgammaRIIb. Because this latter receptor is required for feedback inhibition, a deficient expression might contribute to humoral autoimmune responses. Furthermore, these molecules are likely to be influenced by inflammatory factors, since they were modulated by TNF inhibition.
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Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Antígeno B7-2/metabolismo , Receptores de IgG/metabolismo , Adalimumab , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Autoanticorpos/sangue , Linfócitos B/imunologia , Linfócitos B/metabolismo , Feminino , Humanos , Articulações/fisiopatologia , Pessoa de Meia-Idade , Peptídeos Cíclicos/imunologia , Índice de Gravidade de Doença , Vimentina/imunologiaRESUMO
BACKGROUND: Behçet's disease (BD) is a rare multisystemic inflammatory disease that is potentially disabling and may cause death. AIM: To describe the characteristics of BD patients from two Chilean centers. PATIENTS AND METHOD: Retrospective review of the clinical records of patients with BD attended in two rheumatology services between 1985 and 2007. The "Behçet's Disease Research Committee of Japan" (BDCJ) and the "International Study Group for Behçet's Disease" (ISG) diagnostic criteria were applied. RESULTS: We found 44 cases (25 males), diagnosed as BD. The mean age at the onset of symptoms was 26+/- 12 years. According to BDCJ criteria, 13 patients had complete BD, 24 had incomplete BD and 7 had a suspected BD. Thirty two patients fulfilled the ISG criteria. Forty two patients (95%) had oral ulcers, 33 (75%) had genital ulcers and 29 (66%) had ophthalmological involvement. Eleven and three patients had symptoms of central and peripheral nervous system involvement, respectively. No gender differences were detected. CONCLUSIONS: The clinical characteristics of these patients were similar to those described abroad, except for a higher frequency of peripheral nervous system involvement and a lower rate of arthritis.
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Síndrome de Behçet/diagnóstico , Adolescente , Adulto , Criança , Chile , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Espanha , Adulto JovemRESUMO
Background: Behget's disease (BD) is a rare multisystemic inflammatory disease that is potentially disabling and may cause death. Aim: To describe the characteristics of BD patients from two Chilean centers. Patients and method: Retrospective review of the clinical records of patients with BD attended in two rheumatology services between 1985 and 2007. The "Behget's Disease Research Committee of Japan" (BDCJ) and the "International Study Group for Behget's Disease" (ISG) diagnostic criteria were applied. Results: We found 44 cases (25 males), diagnosed as BD. The mean age at the onset of symptoms was 26± 12 years. According to BDCJ criteria, 13 patients had complete BD, 24 had incomplete BD and 7 had a suspected BD. Thirty two patients fulfilled the ISG criteria. Forty two patients (95 percent) had oral ulcers, 33 (75 percent) had genital ulcers and 29 (66 percent) had ophthalmological involvement. Eleven and three patients had symptoms of central and peripheral nervous system involvement, respectively. No gender differences were detected. Conclusions: The clinical characteristics of these patients were similar to those described abroad, except for a higher frequency of peripheral nervous system involvement and a lower rate of arthritis.