RESUMEN
BACKGROUND: T(H)17 cells play a critical role in the pathogenesis of several autoimmune and allergic diseases. Intravenous immunoglobulin (IVIg), a therapeutic preparation of polyclonal IgG that is increasingly used in the treatment of diverse autoimmune and allergic diseases, might target T(H)17 cells to exert therapeutic effects. OBJECTIVE: We sought to examine whether IVIg interferes with the development and function of human T(H)17 cells. METHODS: T(H)17 cells were differentiated from naive human CD4(+) T cells in the presence of TGF-ß and IL-21. T(H)17 cells were amplified by stimulating memory CD4(+) T cells in the presence of IL-1ß and IL-6. The effect of IVIg was examined on the differentiation and amplification of T(H)17 cells, expression of the T(H)17 lineage-specific transcription factor retinoic acid-related orphan receptor C, secretion of T(H)17 effector cytokines, and phosphorylation of signal transducer and activator of transcription 3, a transcription factor that plays an important role in T(H)17 cell development and function. RESULTS: IVIg inhibits the differentiation and amplification of human T(H)17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21, and CCL20. The inhibitory effects of IVIg on T(H)17 cells are F(ab')(2) dependent and involve interference with the expression of retinoic acid-related orphan receptor C and activation of signal transducer and activator of transcription 3. Also, IVIg significantly enhanced forkhead box protein 3-positive regulatory T cells among the memory CD4(+) T cells. CONCLUSION: These results reveal a novel mechanism of action of IVIg in achieving a therapeutic effect in autoimmune and allergic diseases, in which T(H)17 cells play a key modulatory role in sustaining the chronic inflammatory response. Our results also suggest a reciprocal regulation of T(H)17 and regulatory T-cell populations by IVIg.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Inmunoglobulinas Intravenosas/farmacología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Proliferación Celular/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Humanos , Inmunoglobulinas Intravenosas/inmunología , Transducción de Señal/efectos de los fármacosRESUMEN
Common variable immunodeficiency (CVID) is associated with low serum immunoglobulin concentrations and an increased susceptibility to infections and autoimmune diseases. The treatment of choice for CVID patients is replacement intravenous immunoglobulin (IVIg) therapy. IVIg has been beneficial in preventing or alleviating the severity of infections and autoimmune and inflammatory process in majority of CVID patients. Although the mechanisms of action of IVIg given as 'therapeutic high dose' in patients with autoimmune diseases are well studied, the underlying mechanisms of beneficial effects of IVIg in primary immunodeficiencies are not completely understood. Therefore we investigated the effect of 'replacement dose' of IVIg by probing its action on B cells from CVID patients. We demonstrate that IVIg at low doses induces proliferation and immunoglobulin synthesis from B cells of CVID patients. Interestingly, B cell stimulation by IVIg is not associated with induction of B cell effector cytokine IFN-γ and of transcription factor T-bet. Together, our results indicate that in some CVID patients, IVIg rectifies the defective signaling of B cells normally provided by T cells and delivers T-independent signaling for B cells to proliferate. IVIg 'replacement therapy' in primary immunodeficiencies is therefore not a merepassive transfer of antibodies to prevent exclusively the recurrent infections; rather it has an active role in regulating autoimmune and inflammatory responses through modulating B cell functions and thus imposing dynamic equilibrium of the immune system.
Asunto(s)
Formación de Anticuerpos/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Inmunodeficiencia Variable Común/tratamiento farmacológico , Inmunoglobulinas Intravenosas/farmacología , Adulto , Anciano , Linfocitos B/inmunología , Proliferación Celular/efectos de los fármacos , Separación Celular , Inmunodeficiencia Variable Común/inmunología , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
An altered immune homeostasis as a result of deficiency or defective function of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) is common in several autoimmune diseases. Hence, therapeutic strategies to render Tregs functionally competent are being investigated. Intravenous immunoglobulin (IVIG) is being increasingly used for the treatment of a wide range of autoimmune and inflammatory diseases. Recent studies have demonstrated that IVIG induces the expansion of Tregs and enhances their suppressive functions. These effects of IVIG on Tregs correlate with the beneficial effects of IVIG in patients with autoimmune diseases. Thus, modulation of Tregs by IVIG represents a novel mode of action that explains the therapeutic effects of IVIG in T cell-mediated autoimmune diseases. However, the molecular mechanisms involved in IVIG-mediated modulation of Tregs are unclear and need further investigation.
Asunto(s)
Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Humanos , Inmunidad Celular , Inflamación/inmunología , Inflamación/terapia , Ratones , Modelos Inmunológicos , Linfocitos T Reguladores/trasplanteAsunto(s)
Proteínas Bacterianas/inmunología , Pared Celular/inmunología , Células Dendríticas/inmunología , Interferón gamma/inmunología , Mycobacterium tuberculosis/inmunología , Citocinas/inmunología , Humanos , Proteínas Recombinantes/inmunología , Receptor Toll-Like 2/metabolismo , Vacunas contra la Tuberculosis/inmunologíaAsunto(s)
Predisposición Genética a la Enfermedad , Proteínas Supresoras de la Señalización de Citocinas/genética , Linfocitos T Reguladores/fisiología , Expresión Génica , Humanos , Polimorfismo de Nucleótido Simple , Factor de Transcripción STAT5/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
Intravenous immunoglobulin (IVIg) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. Although a considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory functions in these diseases, they remain not fully elucidated. The mode of action of IVIg is complex, involving interference with activation of complement and the cytokine network, modulation of: idiotype network, expression of Fc receptors, and activation, differentiation and effector functions of T and B cells and of antigen-presenting cells such as dendritic cells. The therapeutic effects of IVIg most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy individuals.
Asunto(s)
Inmunoglobulinas Intravenosas/farmacología , Autoanticuerpos/inmunología , Linfocitos B/efectos de los fármacos , Proteínas Inactivadoras de Complemento/farmacología , Citocinas/biosíntesis , Células Dendríticas/efectos de los fármacos , Homeostasis , Humanos , Idiotipos de Inmunoglobulinas/inmunología , Inmunoglobulinas Intravenosas/inmunología , Inmunoglobulinas Intravenosas/fisiología , Receptores de Superficie Celular/inmunología , Receptores Fc/metabolismo , Linfocitos T/efectos de los fármacosRESUMEN
Dendritic cells (DCs) are professional antigen-presenting cells, which have a central role in the initiation of primary immune responses and in maintaining immune tolerance. The functions of DCs can be regulated both by environmental signals as well as signals delivered by endogenous molecules. Recently we have examined regulation of human DCs by B cells via natural IgG antibodies. Natural antibodies (NAbs) are defined as antibodies that circulate in normal individuals in the absence of deliberate immunization or microbial aggression. We demonstrate that the differentiation of DCs is severely impaired in primary immunodeficient patients such as X-linked agammaglobulinemia (XLA) and common variable immunodeficiency (CVID) at least in part due to the deficiency of circulating NAbs. Further, we show that NAbs are able to restore normal phenotypes of DCs from patients with XLA and CVID. Our results suggest that B cells promote bystander DC development through NAbs and the interaction between NAbs and DCs may play a role in steady-state migration of DCs.
Asunto(s)
Células Dendríticas/inmunología , Inmunoglobulina G/fisiología , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Linfocitos B/inmunología , Diferenciación Celular , Inmunodeficiencia Variable Común/inmunología , Células Dendríticas/citología , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Linfocitos T/inmunologíaAsunto(s)
Antituberculosos/uso terapéutico , Mycobacterium tuberculosis , Vacunas contra la Tuberculosis/uso terapéutico , Tuberculosis/epidemiología , Países en Desarrollo , Salud Global , Humanos , Modelos Teóricos , Pobreza , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Tuberculosis/prevención & controlAsunto(s)
Células de la Médula Ósea/metabolismo , Quimiocinas/sangre , Células Dendríticas/metabolismo , Dermatomiositis/sangre , Proteínas Adaptadoras Transductoras de Señales , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/patología , Biomarcadores/sangre , Células de la Médula Ósea/efectos de los fármacos , Proteínas Portadoras/sangre , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Dermatomiositis/patología , Expresión Génica , Humanos , Interferón Tipo I/farmacología , Proteínas de Unión al ARNRESUMEN
Synthetic CpG containing oligodeoxynucleotide Toll like receptor-9 agonist (CpG DNA) activates innate immunity and can stimulate antigen presentation against numerous intracellular pathogens. It was observed that Salmonella Typhimurium growth can be inhibited by the CpG DNA treatment in the murine dendritic cells. This inhibitory effect was mediated by an increased reactive oxygen species production. In addition, it was noted that CpG DNA treatment of dendritic cells during Salmonella infection leads to an increased antigen presentation. Further this increased antigen presentation was dependent on the enhanced reactive oxygen species production elicited by Toll like receptor-9 activation. With the help of an exogenous antigen it was shown that Salmonella antigen could also be cross-presented in a better way by CpG induction. These data collectively indicate that CpG DNA enhance the ability of murine dendritic cells to contain the growth of virulent Salmonella through reactive oxygen species dependent killing.
Asunto(s)
Antígenos Bacterianos/inmunología , Células Dendríticas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Salmonella/inmunología , Receptor Toll-Like 9/metabolismo , Islas de CpG , Células Dendríticas/inmunología , HumanosRESUMEN
BACKGROUND: Adjuvants enhance or modify an immune response that is made to an antigen. An antagonist of the chemokine CCR4 receptor can display adjuvant-like properties by diminishing the ability of CD4+CD25+ regulatory T cells (Tregs) to down-regulate immune responses. METHODOLOGY: Here, we have used protein modelling to create a plausible chemokine receptor model with the aim of using virtual screening to identify potential small molecule chemokine antagonists. A combination of homology modelling and molecular docking was used to create a model of the CCR4 receptor in order to investigate potential lead compounds that display antagonistic properties. Three-dimensional structure-based virtual screening of the CCR4 receptor identified 116 small molecules that were calculated to have a high affinity for the receptor; these were tested experimentally for CCR4 antagonism. Fifteen of these small molecules were shown to inhibit specifically CCR4-mediated cell migration, including that of CCR4(+) Tregs. SIGNIFICANCE: Our CCR4 antagonists act as adjuvants augmenting human T cell proliferation in an in vitro immune response model and compound SP50 increases T cell and antibody responses in vivo when combined with vaccine antigens of Mycobacterium tuberculosis and Plasmodium yoelii in mice.