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1.
Immunol Lett ; 97(2): 181-8, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15752556

RESUMO

Mucosal immunisation may be used both to protect the mucosal surfaces against infections and as a means for immunological treatment of peripheral immunopathological disorders through the induction of systemic antigen-specific tolerance ('oral tolerance'). The development of mucosal vaccines, whether for prevention of infectious diseases or for oral tolerance immunotherapy, requires efficient antigen delivery and adjuvant systems that can help to present the appropriate vaccine or immunotherapy antigens to the mucosal immune system. The most potent (but also toxic) mucosal adjuvants are cholera toxin (CT) and the closely related Escherichia coli heat-labile enterotoxin (LT), and much effort and significant progress have been made recently to generate toxicologically acceptable derivatives of these toxins with retained adjuvant activity. Among these are the non-toxic, recombinantly produced cholera toxin B-subunit (CTB). CTB is a specific protective antigen component of a widely registered oral cholera vaccine as well as a promising vector for either giving rise to mucosal anti-infective immunity or for inducing peripheral anti-inflammatory tolerance to chemically or genetically linked foreign antigens administered mucosally. CT and CTB have also recently been used as combined vectors and adjuvants for markedly promoting ex vivo dendritic cell (DC) vaccination with different antigens and also steering the immune response to the in vivo-reinfused DCs towards either broad Th1 + Th2 + CTL immunity (CT) or Th2 or tolerance (CTB). Another type of mucosal adjuvants is represented by bacterial DNA or synthetic oligodeoxynucleotides containing CpG-motifs, which especially when linked to CTB have been found to effectively stimulate both innate and adaptive mucosal immune responses. The properties and clinical potential of these different classes of adjuvants are being discussed.


Assuntos
Adjuvantes Imunológicos , Toxina da Cólera/imunologia , Ilhas de CpG/imunologia , Vacinas/imunologia , Animais , Síndrome de Behçet/imunologia , Síndrome de Behçet/prevenção & controle , Toxina da Cólera/química , Ilhas de CpG/genética , Humanos , Imunidade nas Mucosas/imunologia
2.
Arthritis Res Ther ; 10(4): R97, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18718031

RESUMO

INTRODUCTION: The tumour necrosis factor (TNF) family ligands BAFF (B-cell activating factor of TNF family) and APRIL (a proliferation-inducing ligand) are essential for B-cell survival and function. Elevated serum levels of BAFF and APRIL have been reported earlier in patients with systemic lupus erythematosus (SLE). Since autoantibody formation in the central nervous system (CNS) is a distinct feature of neuropsychiatric SLE (NPSLE), we have investigated whether NPSLE is associated with an enhanced intrathecal production of APRIL and BAFF. METHODS: Levels of BAFF and APRIL in cerebrospinal fluid (CSF) and serum from healthy controls, SLE patients without CNS involvement, and patients with NPSLE were determined by enzyme-linked immunosorbent assay. Interleukin-6 (IL-6) levels were determined by an IL-6-specific bioassay. RESULTS: SLE patients had levels of APRIL in CSF that were more than 20-fold higher and levels of BAFF in CSF that were more than 200-fold higher than those of healthy controls. Separate analyses of SLE patients with and without CNS involvement revealed that NPSLE patients had enhanced levels of APRIL in CSF. BAFF and APRIL were likely produced locally in the CNS as CSF and serum levels did not correlate. Moreover, CSF levels of APRIL correlated with BAFF but not with IL-6, suggesting that APRIL and BAFF in the CNS are regulated together but that they are produced independently of IL-6. CONCLUSION: To our knowledge this is the first study to show elevated levels of BAFF and APRIL in CSF of SLE patients. APRIL was augmented in NPSLE patients compared with SLE patients without CNS involvement. APRIL and BAFF antagonists breeching the blood-brain barrier therefore could have beneficial effects on SLE patients, in particular patients with NPSLE.


Assuntos
Fator Ativador de Células B/líquido cefalorraquidiano , Lúpus Eritematoso Sistêmico/líquido cefalorraquidiano , Vasculite Associada ao Lúpus do Sistema Nervoso Central/líquido cefalorraquidiano , Vasculite Associada ao Lúpus do Sistema Nervoso Central/etiologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/líquido cefalorraquidiano , Adulto , Idoso , Fator Ativador de Células B/sangue , Barreira Hematoencefálica/fisiopatologia , Estudos de Casos e Controles , Sistema Nervoso Central/fisiopatologia , Feminino , Humanos , Interleucina-6/sangue , Interleucina-6/líquido cefalorraquidiano , Lúpus Eritematoso Sistêmico/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Masculino , Pessoa de Meia-Idade , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adulto Jovem
3.
Eur J Immunol ; 38(4): 1118-26, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18383034

RESUMO

Dendritic cells (DC) express a functional NADPH oxidase and produce reactive oxygen species (ROS) upon interaction with microbes and T cells. Exposure to ROS leads to DC activation and maturation, as evidenced by phenotypic and functional changes. We have evaluated how endogenous ROS production affects the cytokine secretion pattern and T cell-activating capacity of bone marrow-derived murine DC. DC treated with ROS scavengers, as well as DC from mice that lack a functional NADPH oxidase (and thereby inherently deficient in ROS production) produced significantly increased levels of IL-1beta, IL-6, TNF-alpha and TGF-beta in response to microbial activation. DC deficient in ROS production induced high levels of IFN-gamma and IL-17 in responding T cells after Ag-specific or superantigen-induced activation. Finally, we show that ROS deficiency affected the induction of a T cell-dependent inflammatory condition, collagen-induced arthritis (CIA). C57BL/6 mice that lack a functional NADPH oxidase developed a severe and erosive CD4-dependent CIA, whereas the majority of the congenic wild-type animals remained healthy. These data suggest that ROS act as immunomodulators in DC-driven T cell activation and perhaps also in T cell-dependent immunopathology.


Assuntos
Artrite/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Interleucina-17/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Colágeno Tipo II/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/metabolismo , Interferon gama/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/deficiência , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo
4.
Immunology ; 118(3): 311-20, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16827892

RESUMO

Oral administration of antigens coupled to the B subunit of the cholera toxin (CTB) can dramatically reduce the amount of antigen needed for tolerance induction and has been used in several animal models to suppress conditions where the immune system overreacts to foreign and self-antigens. In this study, the cellular events following oral administration of CTB-coupled antigen was investigated. As a model system, limited numbers of CSFE-labelled cells from influenza haemagglutinin peptide (HApep) T-cell transgenic mice were transferred to wild type mice and the mice were then given CTB-coupled HApep orally. The inductive events of CTB-induced tolerance was characterized by extensive proliferation of HApep-specific T cells in the mesenteric lymph nodes (MLNs) and in the spleen. The proliferating cells up-regulated the gut homing molecule alpha4beta7 and down-regulated the high endothelial venule binding molecule L-selectin. Addition of the whole cholera toxin (CT) to CTB-HApep showed a similar pattern as CTB-HApep feeding, with antigen-specific proliferation in the MLN and spleen and expression of alpha4beta7 on the proliferating cells. However, addition of CT to CTB-HApep, produced a stronger and faster proliferative response and abrogated CTB-HA mediated oral tolerance. Feeding of CTB-HApep expanded CD25+ cells in the MLNs. CTB-induced oral tolerance could, however, not be explained by CD25+ dependent regulatory activity, as oral administration of CTB-HApep to mice depleted of CD25+ cells still gave rise to systemic tolerance. Thus, several mechanisms might co-orchestrate the systemic tolerance seen in response to feeding with CTB-coupled antigen.


Assuntos
Toxina da Cólera/imunologia , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Administração Oral , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Regulação para Baixo/imunologia , Hemaglutininas Virais/imunologia , Imunidade nas Mucosas , Integrinas/metabolismo , Selectina L/metabolismo , Linfonodos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptores de Interleucina-2/análise , Baço/imunologia , Regulação para Cima/imunologia
5.
J Immunol ; 170(3): 1586-92, 2003 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-12538724

RESUMO

Topical application of cholera toxin (CT) onto mouse skin can induce a humoral immune response to CT as well as to coadministered Ags. In this study, we examined the nontoxic cell-binding B subunit of CT (CTB) as a potential adjuvant for cutaneous immune responses when coadministered with the prototype protein Ag, OVA. CTB applied onto skin induced serum Ab responses to itself with magnitudes comparable to those evoked by CT but was poorly efficient at promoting systemic Ab responses to coadministered OVA. However, transcutaneous immunization (TCI) with either CT or CTB and OVA led to vigorous OVA-specific T cell proliferative responses. Furthermore, CTB potentiated Th1-driven responses (IFN-gamma production) whereas CT induced both Th1 and Th2 cytokine production. Coadministration of the toxic subunit CTA, together with CTB and OVA Ag, led to enhanced Th1 and Th2 responses. Moreover, whereas TCI with CT enhanced serum IgE responses to coadministered OVA, CTB suppressed these responses. TCI with either CT or CTB led to an increased accumulation of dendritic cells in the exposed epidermis and the underlying dermis. Thus, in contrast to CT, CTB appears to behave very differently when given by the transcutaneous as opposed to a mucosal route and the results suggest that the adjuvanticity of CT on Th1- and Th2-dependent responses induced by TCI involves two distinct moieties, the B and the A subunits, respectively.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Toxina da Cólera/administração & dosagem , Toxina da Cólera/imunologia , Regulação para Baixo/imunologia , Imunoglobulina E/biossíntese , Imunossupressores/administração & dosagem , Ativação Linfocitária/imunologia , Células Th1/imunologia , Administração Cutânea , Alérgenos/administração & dosagem , Alérgenos/imunologia , Animais , Antígenos CD/biossíntese , Antígeno B7-1/biossíntese , Antígeno B7-2 , Contagem de Células , Relação Dose-Resposta Imunológica , Sinergismo Farmacológico , Células Epidérmicas , Epiderme/imunologia , Feminino , Imunização/métodos , Imunoglobulina E/sangue , Imunossupressores/imunologia , Células de Langerhans/citologia , Células de Langerhans/imunologia , Glicoproteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Regulação para Cima/imunologia
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