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1.
Front Immunol ; 9: 1119, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875774

RESUMO

T-cell-mediated immune responses play a fundamental role in controlling Mycobacterium tuberculosis (M. tuberculosis) infection, and traditionally, this response is thought to be mediated by Th1-type CD4+ T-cells secreting IFN-γ. While studying the function and specificity of M. tuberculosis-reactive CD4+ T-cells in more detail at the single cell level; however, we found a human CD4+ T-cell population with a naive phenotype that interestingly was capable of producing multiple cytokines (TCNP cells). CD4+ TCNP cells phenotyped as CD95lo CD28int CD49dhi CXCR3hi and showed a broad distribution of T cell receptor Vß segments. They rapidly secreted multiple cytokines in response to different M. tuberculosis antigens, their frequency was increased during active disease, but was comparable to latent tuberculosis infection in treated TB patients. These results identify a novel human CD4+ T-cell subset involved in the human immune response to mycobacteria, which is present in active TB patients' blood. These results significantly expand our understanding of the immune response in infectious diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Imunofenotipagem , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/metabolismo , Adulto , Antígenos de Bactérias/imunologia , Contagem de Linfócito CD4 , Progressão da Doença , Feminino , Humanos , Masculino , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose/microbiologia , Adulto Jovem
2.
Biomed Rep ; 6(3): 314-318, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28451392

RESUMO

Stem cells are an important tool for the study of hematopoiesis. Despite developments in cryopreservation, post-thaw cell death remains a considerable problem. Cryopreservation protocol should limit cell damage due to freezing and ensure the recovery of the functional cell characteristics after thawing. Thus, the use of cryoprotectants is essential. In particular, the efficacy of trehalose has been reported for clinical purposes in blood stem cells. The aim of the current study was to establish an efficient method for biological research based on the use of trehalose, to cryopreserve pure peripheral blood stem cells. The efficacy of trehalose was assessed in vitro and the cell viability was evaluated. The data indicate that trehalose improves cell survival after thawing compared with the standard freezing procedure. These findings could suggest the potential for future trehalose application for research purposes in cell cryopreservation.

3.
Cancer Immunol Res ; 5(5): 397-407, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28351891

RESUMO

The identification of reciprocal interactions between tumor-infiltrating immune cells and the microenviroment may help us understand mechanisms of tumor growth inhibition or progression. We have assessed the frequencies of tumor-infiltrating and circulating γδ T cells and regulatory T cells (Treg) from 47 patients with squamous cell carcinoma (SCC), to determine if they correlated with progression or survival. Vδ1 T cells infiltrated SSC tissue to a greater extent than normal skin, but SCC patients and healthy subjects had similar amounts circulating. However, Vδ2 T cells were present at higher frequencies in circulation than in the tissue of either cancer patients or healthy donors. Tregs were decreased in the peripheral blood of SCC patients, but were significantly increased in the tumor compartment of these patients. Tumor-infiltrating γδ T cells preferentially showed an effector memory phenotype and made either IL17 or IFNγ depending on the tumor stage, whereas circulating γδ T cells of SCC patients preferentially made IFNγ. Different cell types in the tumor microenvironment produced chemokines that could recruit circulating γδ T cells to the tumor site and other cytokines that could reprogram γδ T cells to produce IL17. These findings suggest the possibility that γδ T cells in SCC are recruited from the periphery and their features are then affected by the tumor microenvironment. Elevated frequencies of infiltrating Vδ2 T cells and Tregs differently correlated with early and advanced tumor stages, respectively. Our results provide insights into the functions of tumor-infiltrating γδ T cells and define potential tools for tumor immunotherapy. Cancer Immunol Res; 5(5); 397-407. ©2017 AACR.


Assuntos
Carcinoma de Células Escamosas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Cutâneas/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia , Microambiente Tumoral
4.
PLoS One ; 11(2): e0149570, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26915072

RESUMO

OBJECTIVE: The aim of this study was to evaluate over time circulating γδ T lymphocytes in melanoma patients in terms of frequency, effector functions, and relationship with clinical stage and evolution, by comparing preoperative values to those obtained at a mean follow-up of 36 months or in the event of recurrence or disease progression, and to those of healthy controls. Also, we correlated the presence of tumor-infiltrating γδ T lymphocytes with clinical evolution of melanoma. RESULTS: Mean frequencies of circulating γδ T cells before and after melanoma removal were very similar and comparable to healthy subjects, but patients who progressed to stage III or IV showed a significantly decreased frequency of circulating Vγ9Vδ2 T cells. The distribution of Vγ9Vδ2 memory and effector subsets was similar in healthy subjects and melanoma patients at diagnosis, but circulating γδ T cells of patients after melanoma removal had a skewed terminally-differentiated effector memory phenotype. Highly suggestive of progressive differentiation toward a cytotoxic phenotype, Vγ9Vδ2T cells from patients at follow up had increased cytotoxic potential and limited cytokine production capability, while the opposite pattern was detected in Vγ9Vδ2T cells from patients before melanoma removal. CONCLUSIONS: Follow-up data also showed that tumor infiltrating γδ T cells were significantly associated with lower mortality and relapse rates, suggesting that they may serve as a prognostic biomarker, for human melanoma.


Assuntos
Diferenciação Celular , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma/diagnóstico , Melanoma/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Melanoma/sangue , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Prognóstico
5.
Cell Transplant ; 25(2): 353-64, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25994834

RESUMO

The epidermis is a stratified epithelium with a stem cell subpopulation in the basal layer that constantly replicates and periodically detaches from the base, undergoing a differentiation process that involves various developmental signals and regulatory pathways. During the last 10 years, a number of studies tried to elucidate the intricate scenario that maintains the epithelial shield during the entire life span. In our study, we investigated the role of Numb in the skin compartment and, in particular, its involvement in stem cell maintenance. Numb expression in the skin compartment was assessed by immunofluorescence and immunohistochemistry analysis. We evaluated Numb expression in primary epithelial cells at various differentiative stages. Moreover, we overexpressed Numb in the isolated population enriched for undifferentiated progenitors to establish its involvement in in vitro differentiation. We demonstrated that Numb in high-proliferating epithelial undifferentiated progenitors contributes to the maintenance of an undifferentiated state. This regulation involves the E3 ligases Itch binding. Moreover, the analysis of a cohort of cutaneous carcinomas showed that Numb is highly expressed in squamous cell carcinoma (SCC), where we observed a direct correlation between the expression of Numb and Ki-67. Our data indicate for the first time that Numb is involved in the maintenance of the undifferentiated proliferating stem cell pool in the epithelial basal layer and its expression could become a new marker in skin cancer.


Assuntos
Carcinoma de Células Escamosas/patologia , Epiderme/metabolismo , Células Epiteliais/citologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Diferenciação Celular , Proliferação de Células/fisiologia , Epiderme/patologia , Células Epiteliais/metabolismo , Humanos , Imuno-Histoquímica/métodos , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética
6.
Mol Cancer ; 14: 155, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26272696

RESUMO

BACKGROUND: CD90+ liver cancer cells have been described as cancer stem-cell-like (CSC), displaying aggressive and metastatic phenotype. Using two different in vitro models, already described as CD90+ liver cancer stem cells, our aim was to study their interaction with endothelial cells mediated by the release of exosomes. METHODS: Exosomes were isolated and characterized from both liver CD90+ cells and hepatoma cell lines. Endothelial cells were treated with exosomes, as well as transfected with a plasmid containing the full length sequence of the long non-coding RNA (lncRNA) H19. Molecular and functional analyses were done to characterize the endothelial phenotype after treatments. RESULTS: Exosomes released by CD90+ cancer cells, but not by parental hepatoma cells, modulated endothelial cells, promoting angiogenic phenotype and cell-to-cell adhesion. LncRNA profiling revealed that CD90+ cells were enriched in lncRNA H19, and released this through exosomes. Experiments of gain and loss of function of H19 showed that this LncRNA plays an important role in the exosome-mediated phenotype of endothelial cells. CONCLUSIONS: Our data indicate a new exosome-mediated mechanism by which CSC-like CD90+ cells could influence their tumor microenvironment by promoting angiogenesis. Moreover, we suggest the lncRNA H19 as a putative therapeutic target in hepatocellular carcinoma.


Assuntos
Células Endoteliais/metabolismo , Exossomos/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fenótipo , RNA Longo não Codificante/genética , Antígenos Thy-1/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos
7.
Immunotherapy ; 6(9): 989-99, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25341120

RESUMO

γδ T cells are capable of recognizing tumor cells and exert potent cellular cytotoxicity against a large range of tumors, including colon cancer. However, tumors utilize numerous strategies to escape recognition or killing by patrolling γδ T cells, such a downregulation of NKG2D ligands, MICA/B and ULBPs. Therefore, the combined upregulation of T-cell receptorand NKG2D ligands on tumor cells and induction of NKG2D expression on γδ T cells may greatly enhance tumor killing and unlock the functions of γδ T cells. Here, we briefly review current data on the mechanisms of γδ T-cell recognition and killing of colon cancer cells and propose that γδ T cells may represent a promising target for the design of novel and highly innovative immunotherapy in patients with colon cancer.


Assuntos
Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Imunoterapia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Citotoxicidade Imunológica , Humanos , Ligantes , Células-Tronco Neoplásicas/imunologia , Subpopulações de Linfócitos T/imunologia
8.
Leuk Res ; 37(12): 1616-21, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24183830

RESUMO

CD200 is a relatively ubiquitously expressed molecule that plays a role in cancer immune evasion through interaction with its receptors. High expression levels of CD200 have been described in different human malignancies. For example, CD200 has been shown to be targeted after RAS/RAF/MEK/ERK activation in melanoma. Here we present the analysis of CD200 expression in human Multiple Myeloma (MM) samples. We found that CD200-positive cells express ERK and p-ERK. Moreover, UO126, a MEK inhibitor, reduces CD200 expression. Furthermore, we observe that CD200-positive cells show reduced immunogenicity compared to normal lymphocytes and that such immunogenicity increases when UO126 is used. We therefore hypothesize that CD200 expression in MM could suppress antitumor response and that anti-CD200 treatment might be therapeutically beneficial in CD200-expressing tumors.


Assuntos
Antígenos CD/metabolismo , Mieloma Múltiplo/metabolismo , Antígenos de Superfície/metabolismo , Biomarcadores Tumorais/metabolismo , Butadienos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Teste de Cultura Mista de Linfócitos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Nitrilas/farmacologia , Receptores de Orexina , Receptores de Superfície Celular/metabolismo , Evasão Tumoral/fisiologia
10.
Int J Cancer ; 131(9): 2197-203, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22322883

RESUMO

Disulfiram (DSF) is an aldehyde dehydrogenase inhibitor currently used for the treatment of alcoholism. Here, we show that multiple myeloma (MM) cell lines and primary cells from newly diagnosed and relapsed/resistant patients affected by MM, acute myeloid and lymphoblastic leukemia are significantly sensitive to DSF alone and in combination with copper. These effects are present at doses lower than those achievable in vivo after DSF standard administration. The cytotoxic effect achieved by this treatment is comparable to that obtained by conventional chemotherapy and is absent in normal hematopoietic cells. In addition, we found that DSF plus copper induces loss of mitochondrial membrane potential, triggers reactive oxygen species (ROS) production and activates executioner caspases. DSF-copper-induced apoptosis and caspases activation are strongly reversed by antioxidant N-acetylcysteine, thus indicating a critical role of ROS. These results might suggest the use of the old drug DSF, alone or in combination with copper, in the treatment of hematological malignancies.


Assuntos
Antineoplásicos/farmacologia , Cobre/farmacologia , Dissulfiram/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Acetilcisteína/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Caspases/biossíntese , Linhagem Celular Tumoral , Dissulfiram/uso terapêutico , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Potenciais da Membrana/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Estresse Oxidativo/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Espécies Reativas de Oxigênio/metabolismo
11.
Tuberculosis (Edinb) ; 89(1): 91-4, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18986840

RESUMO

We report that a recently developed combined immunotherapy (CIT) has the capacity to prevent a spontaneous relapse of replicating Mycobacterium tuberculosis bacilli in the lungs of BALB/c, C57Bl/6 or C3H/HeJ strains of mice, following 4weeks of non-sterilising treatment with isoniazid and rifampicin. The CIT regimen, represented by recombinant IFNgamma, anti-alpha crystalline monoclonal IgA antibody and IL-4 neutralizing polyclonal antibody, reduced the 8-week relapse of viable bacterial counts in the lungs most significantly, when CIT was inoculated during the 5th week post infection, i.e. during the 3rd week of chemotherapy. Although CIT enhanced lung granuloma area, nitric oxide, cytokine and chemokine levels in lung washings significantly, these could not be directly associated with the beneficial effect of CIT on the degree of relapse in the lungs. These results represent a proof-of-principle, that the described CIT, when combined with chemotherapy, could have potential for future development of a shorter regimen of tuberculosis treatment.


Assuntos
Antituberculosos/uso terapêutico , Imunoterapia/métodos , Mycobacterium tuberculosis , Tuberculose Pulmonar/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Animais , Anticorpos/uso terapêutico , Contagem de Colônia Microbiana , Terapia Combinada , Imunoglobulina A/uso terapêutico , Interferon gama/uso terapêutico , Interleucina-4/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Modelos Animais , Proteínas Recombinantes , Recidiva , Tuberculose Pulmonar/terapia , alfa-Cristalinas/imunologia
12.
J Med Chem ; 51(21): 6800-7, 2008 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-18937434

RESUMO

A small series of aminobisphosphonates (N-BPs) structurally related to zoledronic acid was synthesized with the aim of improving activity toward activation of human gammadelta T cells and in turn their in vivo antitumor activity. The absence of the 1-OH moiety, together with the position and the different basicity of the nitrogen, appears crucial for antitumor activity. In comparison to zoledronic acid, compound 6a shows a greater ability to activate gammadelta T cells expression (100 times more) and a proapoptotic effect that is better than zoledronic acid. The potent activation of gammadelta T cells, in addition to evidence of the in vivo antitumor activity of 6a, suggests it may be a new potential drug candidate for cancer treatment.


Assuntos
Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Difosfonatos/síntese química , Difosfonatos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Difosfonatos/química , Desenho de Fármacos , Humanos , Ativação Linfocitária/imunologia , Camundongos , Camundongos SCID , Estrutura Molecular , Relação Estrutura-Atividade
13.
Cancer Res ; 67(15): 7450-7, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17671215

RESUMO

The increasing evidence that gammadelta T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the gammadelta T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood gammadelta cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral gammadelta cells toward an activated effector-memory-like state (T(EM)), producing IFN-gamma and perforin. These patients also maintained serum levels of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by gammadelta cells activated via the T-cell receptor and IL-2. Moreover, the numbers of T(EM) gammadelta cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either gammadelta cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, gammadelta cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma.


Assuntos
Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Imunoterapia/métodos , Interleucina-2/uso terapêutico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Receptores de Antígenos de Linfócitos T gama-delta , Linfócitos T/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Estudos de Viabilidade , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Terapia de Salvação , Linfócitos T/citologia , Linfócitos T/imunologia , Resultado do Tratamento , Ácido Zoledrônico
14.
Clin Vaccine Immunol ; 14(9): 1231-4, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17626158

RESUMO

Serum responses against Mycobacterium tuberculosis HSP16 were determined for children with tuberculosis (TB) and for healthy purified protein derivative (PPD)-positive and PPD-negative children. Immunoglobulin G (IgG) and IgM responses were higher for TB patients than for other groups. After chemotherapy, IgM and IgG responses decreased for TB patients and PPD-positive subjects. Monitoring of anti-M. tuberculosis HSP16 responses could assist in the management of pediatric TB.


Assuntos
Antituberculosos/uso terapêutico , Proteínas de Bactérias/imunologia , Chaperoninas/imunologia , Imunoglobulina M/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculina/imunologia , Tuberculose/prevenção & controle , Adolescente , Quimioprevenção , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/biossíntese , Imunoglobulina M/sangue , Tuberculose/sangue , Tuberculose/imunologia
15.
Tuberculosis (Edinb) ; 87(4): 322-8, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17379576

RESUMO

Granulysin is a cytolytic protein of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Serum levels of granulysin are related to host cellular immunity. We used an ELISA to quantify granulysin serum levels in children with tuberculosis (TB), before and after chemotherapy. The study involved children affected by different clinical forms of TB (n=72) and healthy control children (n=150) from the same geographical area and of similar socio-economic background. Serum granulysin levels before the initiation of TB therapy were significantly lower in children with TB compared to controls, with the lowest levels being found in TB patients who were PPD skin test negative. No statistically significant differences were found between serum granulysin levels and clinical severity (mild/moderate or advanced pulmonary TB) or the clinical form (pulmonary or extra-pulmonary) of TB. At four months after completion of therapy, serum granulysin levels in children treated for TB were not significantly different to those observed in control children. This finding was paralleled by the increased in vitro mycobactericidal activity of sera from TB patients after completion of therapy. We propose that serum granulysin levels may provide a marker of disease activity in childhood TB and might be useful for monitoring improvement after chemotherapy.


Assuntos
Antígenos de Diferenciação de Linfócitos T/sangue , Biomarcadores/sangue , Tuberculose Pulmonar/sangue , Tuberculose/sangue , Antituberculosos/uso terapêutico , Criança , Pré-Escolar , Técnicas de Cocultura , Feminino , Humanos , Masculino , Tuberculose Meníngea/sangue , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico
16.
Eur J Immunol ; 37(3): 729-37, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17304630

RESUMO

The influence of Th2 cytokines in tuberculosis has been a matter of dispute. Here we report that IL-4 has a profound regulatory effect on the infection of BALB/c mice with Mycobacterium tuberculosis. Depletion of IL-4 with a neutralizing mAb caused only evanescent reduction of lung infection, but when combined with i.n. inoculations of IgA anti-mycobacterial alpha-crystallin mAb and mouse rIFN-gamma, we observed a 40-fold reduction of the bacterial counts in the lungs at 3 wks following i.n. infection (p<0.001). In genetically deficient IL-4-/- BALB/c mice, infection in both lung and spleen was substantially reduced for up to 8 wks without further treatment. Reconstitution of IL-4-/- mice with rIL-4 increased bacterial counts to wild-type levels and made the mice refractory to protection by IgA/IFN-gamma. Analysis of the lungs showed increased granulomatous infiltration and proinflammatory mediators in anti-IL-4/IgA/IFN-gamma-treated and infected mice. We conclude that the action of IL-4 in tuberculosis is targeted at macrophages and that it may include an antagonistic effect on their IgA/IFN-gamma-induced activation and nitric oxide production. The described novel immunotherapy, combining treatments with anti-IL-4, IgA antibody and IFN-gamma, has potential for translation toward the passive immunoprophylaxis of tuberculosis.


Assuntos
Imunização Passiva , Imunoglobulina A/fisiologia , Interleucina-4/antagonistas & inibidores , Interleucina-4/deficiência , Tuberculose Pulmonar/imunologia , Animais , Imunidade Inata , Imunoglobulina A/uso terapêutico , Interferon gama/antagonistas & inibidores , Interferon gama/fisiologia , Interleucina-4/genética , Interleucina-4/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/prevenção & controle
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