RESUMO
The role of IL-17 and Th17 cells in immunity vs. pathology associated with the human commensal Candida albicans remains controversial. Both positive and negative effects on immune resistance have been attributed to IL-17/Th17 in experimental candidiasis. In this study, we provide evidence that IL-22, which is also produced by Th17 cells, has a critical, first-line defense in candidiasis by controlling the growth of infecting yeasts as well as by contributing to the host's epithelial integrity in the absence of acquired Th1-type immunity. The two pathways are reciprocally regulated, and IL-22 is upregulated under Th1 deficiency conditions and vice versa. Whereas both IL-17A and F are dispensable for antifungal resistance, IL-22 mediates protection in IL-17RA-deficient mice, in which IL-17A contributes to disease susceptibility. Thus, our findings suggest that protective immunity to candidiasis is made up of a staged response involving an early, IL-22-dominated response followed by Th1/Treg reactivity that will prevent fungal dissemination and supply memory.
Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Interleucinas/metabolismo , Mucosa Intestinal/imunologia , Células Th1/imunologia , Animais , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Candidíase/genética , Candidíase/metabolismo , Candidíase/patologia , Processos de Crescimento Celular , Células Cultivadas , Humanos , Imunidade nas Mucosas , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucinas/genética , Interleucinas/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Células Th1/microbiologia , Células Th2/imunologia , Células Th2/microbiologia , Interleucina 22RESUMO
We analyzed the contribution of intracellular signaling to the functional plasticity of dendritic cells (DCs) presenting Candida albicans, a human commensal associated with severe diseases. Distinct intracellular pathways were activated by recognition of different fungal morphotypes in distinct DC subsets and in Peyer's patches DCs. Inflammatory DCs initiated Th17/Th2 responses to yeasts through the adaptor myeloid differentiation factor-88 (MyD88), whereas tolerogenic DCs activate Th1/T regulatory cell (Treg) differentiation programs to hyphae involving Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) as an intermediary of signaling. In addition, signal transducer and activator of transcription 3 (STAT3), affecting the balance between canonical and non-canonical activation of nuclear factor-kappaB (NF-kappaB) and 2,3 indoleamine dioxygenase (IDO), pivotally contributed to DC plasticity and functional specialization. As Candida-induced tolerogenic DCs ameliorated experimental colitis, our data qualify Candida as a commensal with immunoregulatory activity, resulting from the orchestrated usage of multiple, yet functionally distinct, receptor-signaling pathways in DCs. Ultimately, affecting the local Th17/Treg balance might likely be exploited by the fungus for either commensalism or pathogenicity.
Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Células Dendríticas/imunologia , Tolerância Imunológica , Inflamação/imunologia , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Células Dendríticas/microbiologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/microbiologia , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , Células Th1/imunologia , Células Th1/microbiologia , Células Th2/imunologia , Células Th2/microbiologiaRESUMO
Chronic granulomatous disease is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections and disordered inflammation. We propose that NADPH oxidase has a key role in regulating acute neutrophilic and T cell responses, which in turn restrains fungal growth and calibrates the inflammatory response to minimize injury and allergy. In this model, superoxide-induced activation of indoleamine 2,3-dioxygenase (IDO) is a central mechanism by which the optimal balance of antifungal host defense and immune tolerance occurs. This model is based on studies in mice and requires correlation in humans.
Assuntos
Infecções Bacterianas/imunologia , Doença Granulomatosa Crônica , Micoses/imunologia , NADPH Oxidases/metabolismo , Animais , Modelos Animais de Doenças , Ativação Enzimática , Doença Granulomatosa Crônica/enzimologia , Doença Granulomatosa Crônica/imunologia , Humanos , Sistema Imunitário/fisiologia , Tolerância Imunológica/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/imunologia , Espécies Reativas de Oxigênio/imunologia , Triptofano/metabolismoRESUMO
The balance of pro- and anti-inflammatory signaling is a prerequisite for successful host/fungal interactions and requires the coordinate actions of both innate and adaptive immune systems. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases and limit protective antifungal immune responses. The newly described Th17 develop - mental pathway may play an inflammatory role previously attributed to uncontrolled Th1 responses and serve to accommodate the seemingly paradoxical association of chronic inflammatory responses with fungal persistence in the face of an ongoing inflammation. In this scenario, unrestricted fungal growth could result from the activation of not only pathogenic Th17 cells, but also Th2 cells whose activation is strictly dependent on fungal burden. The capacity of regulatory T cells (Tregs) to inhibit aspects of innate and adaptive antifungal immunity is required for protective tolerance to fungi. Indoleamine 2,3-dioxygenase (IDO) and tryptophan catabolites contribute to such a homeostatic condition by providing the host with immune defense mechanisms adequate for protection, without necessarily eliminating fungal pathogens - which would impair immune memory - or causing an unacceptable level of tissue damage. IDO and tryptophan metabolites may prove to be potent regulators capable of taming overzealous or heightened inflammatory host responses.
Assuntos
Dermatomicoses/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Pneumopatias Fúngicas/imunologia , Hipersensibilidade Respiratória/imunologia , Linfócitos T Reguladores/enzimologia , Animais , Anticorpos Antifúngicos/biossíntese , Antígenos de Fungos/imunologia , Dermatomicoses/enzimologia , Retroalimentação Fisiológica , Fungos/imunologia , Homeostase , Humanos , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Pneumopatias Fúngicas/enzimologia , Mimetismo Molecular , Hipersensibilidade Respiratória/enzimologia , Hipersensibilidade Respiratória/microbiologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/patologiaRESUMO
Plasmacytoid dendritic cells (pDCs) represent a specialized cell population that produces large amounts of type I interferons, the so-called natural interferon-producing cells. Recently, murine and human pDCs have been credited with a unique ability to express indoleamine 2,3-dioxygenase (IDO) and to mediate immunosuppression in specific settings. This suggests an important role for IDO-expressing pDCs in controlling the balance of inflammation and tolerance. Here we review recent advances in our understanding of how these cells may be critical at the interface of inflammation and tolerance and discuss the potential for therapeutic IDO modulation as an immunoregulatory maneuver targeting pDC function.
Assuntos
Células Dendríticas/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Animais , Apoptose , Células Dendríticas/metabolismo , Humanos , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Linfócitos T/imunologia , Triptofano/imunologia , Triptofano/metabolismoRESUMO
BACKGROUND: Trimetazidine (TMZ) has been shown to partially inhibit free fatty acid oxidation by shifting substrate utilization from fatty acid to glucose. The aim of this study was to assess the effects of TMZ in patients with diabetes and ischemic cardiomyopathy. METHODS: Sixteen patients with diabetes and ischemic hypokinetic cardiomyopathy (all males) on conventional therapy were randomized to receive either placebo or TMZ (20 mg 3 times per day), each arm lasting 15 days, and then again to receive either placebo or TMZ for 2 additional 6-month periods, according to a double-blind, crossover design. At the end of each period, all patients underwent exercise testing, 2-dimensional echocardiography, and hyperinsulinemic/euglycemic clamp. Among the others, New York Heart Association class, ejection fraction, exercise time, fasting blood glucose, end-clamp M value (index of total body glucose disposal) and endothelin-1 levels were evaluated. RESULTS: Both in the short and long term (completed by 13 patients), on TMZ compared to placebo, ejection fraction (47 +/- 7 vs 41 +/- 9 and 45 +/- 8 vs 36 +/- 8%, P <.001 for both) and M value (4.0 +/- 1.8 vs 3.3 +/- 1.6, P =.003, and 3.5 +/- 1.5 vs 2.7 +/- 1.6 mg/kg body weight/min, P <.01) increased, while fasting blood glucose (121 +/- 30 vs 136 +/- 40, P =.02 and 125 +/- 36 vs 140 +/- 43, P =.19) and endothelin-1 (8.8 +/- 3.8 vs 10.9 +/- 3.8, P <.001 and 6.2 +/- 2.4 vs 9.2 +/- 4.3 pg/mL, P =.03) decreased. In the short term, 10 patients decreased 1 class on the NYHA scale during treatment with TMZ (P =.019 vs placebo). Eight patients decreased 1 NYHA class while on long-term TMZ treatment, while on placebo 1 patient increased 1 NYHA class and none improved (P =.018 vs placebo). CONCLUSIONS: In a short series of patients with diabetes and ischemic cardiomyopathy, TMZ improved left ventricular function, symptoms, glucose metabolism, and endothelial function. Shifting energy substrate preference away from fatty acid metabolism and toward glucose metabolism by TMZ appears an effective adjunctive treatment in patients with diabetes with postischemic cardiomyopathy.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Isquemia Miocárdica/complicações , Miocárdio/metabolismo , Trimetazidina/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Ecocardiografia , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/metabolismoRESUMO
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that, expressed by different cell types, has regulatory effects on T cells resulting from tryptophan depletion in specific local tissue microenvironments. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We show here that tryptophan metabolites in the kynurenine pathway, such as 3-hydroxyanthranilic and quinolinic acids, will induce the selective apoptosis in vitro of murine thymocytes and of Th1 but not Th2 cells. T cell apoptosis was observed at relatively low concentrations of kynurenines, did not require Fas/Fas ligand interactions, and was associated with the activation of caspase-8 and the release of cytochrome c from mitochondria. When administered in vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data suggest that the selective deletion of T lymphocytes may be a major mechanism whereby tryptophan metabolism affects immunity under physiopathologic conditions.
Assuntos
Apoptose/fisiologia , Doenças Autoimunes/imunologia , Cinurenina/metabolismo , Tolerância a Antígenos Próprios/imunologia , Linfócitos T/metabolismo , Triptofano/metabolismo , Ácido 3-Hidroxiantranílico/metabolismo , Ácido 3-Hidroxiantranílico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 8 , Caspase 9 , Inibidores de Caspase , Caspases/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Células Cultivadas , Grupo dos Citocromos c/efeitos dos fármacos , Grupo dos Citocromos c/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ácido Quinolínico/metabolismo , Ácido Quinolínico/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/ultraestrutura , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th1/ultraestrutura , Timo/efeitos dos fármacos , Timo/metabolismo , Timo/ultraestrutura , Receptor fas/genética , Receptor fas/metabolismoRESUMO
The role of cytokines in the pathogenesis of T cell-mediated diseases, and in particular autoimmune responses, has been the subject of intense investigation in the past few years. Transgenic strains of mice have been generated, each expressing individual cytokines in organs targeted by autoimmunity. These animal models provide the most advanced tool available for analyzing the relationship between cytokines and T-dependent autoimmune responses. On the one hand, these experiments confirm that the local expression of proinflammatory cytokines is pivotal in initiating and maintaining pathogenic responses to self. On the other hand, and somewhat unexpectedly, these models have also revealed that cytokine factors controlling autoimmunity can act both as potentiating and inhibitory agents, depending upon the site and timing of exposure. As a result, one major concept emerging from different experimental models, including those originally established in our laboratory, is that proinflammatory cytokines may ameliorate autoimmunity. In this review, we analyze the mechanisms whereby cytokines that are considered as proinflammatory may in contrast suppress immune responses to self antigens. Besides emphasizing that the proinflammatory/immunogenic properties of a given cytokine may not be an intrinsic property, we review evidence that the regulation imposed by the cytokine network on autoimmunity is a finely tuned balance between activation and downmodulation of an individual autoreactive T cell repertoire. By emphasizing that factors such as the duration of cytokine exposure and the type of cell population involved strongly influence that balance, we underline the potential therapeutic implications of cytokine-mediated modulation of autoimmunity.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Citocinas/farmacologia , Imunossupressores/farmacologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Doenças Autoimunes/etiologia , Citocinas/uso terapêutico , Células Dendríticas/efeitos dos fármacos , Humanos , Interferon gama/farmacologia , Óxido Nítrico/fisiologia , Triptofano/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
The outcome of dendritic cell (DC) presentation of tumor and/or self peptides, including P815AB (a tumor peptide of murine mastocytoma cells) and NRP-A7 (a synthetic peptide mimotope recognized by diabetogenic T cells), may depend on a balance between the activities of immunogenic (CD8alpha(-)) and tolerogenic (CD8alpha(+)) DC. By virtue of their respective actions on CD8(-) and CD8(+) DC, IL-12 and IFN-gamma have functionally opposing effects on peptide presentation by the CD8(-) DC subset, and IFN-gamma-activated CD8(+) DC mediate tolerogenic effects that prevail over the adjuvant activity of IL-12 on CD8(-) DC. We have previously shown that CD40 ligation abrogates the tolerogenic potential of CD8(+) DC, an effect associated with an impaired capacity of the CD40-modulated and IFN-gamma-treated DC to degrade tryptophan and initiate T cell apoptosis in vitro. We report here that IL-6 may both replace (upon administration of the recombinant cytokine) and mediate (as assessed by the use of neutralizing Abs) the effect of CD40 ligation in ablating the tolerogenic activity of CD8(+) DC. The activity of IL-6 includes down-regulation of IFN-gammaR expression in the CD8(+) DC subset and correlates to a reduced ability of these cells to metabolize tryptophan and initiate T cell apoptosis in vitro.
Assuntos
Antígenos CD8/biossíntese , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Interleucina-6/fisiologia , Triptofano Oxigenase/biossíntese , Animais , Apoptose/imunologia , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Antígenos CD40/fisiologia , Células Cultivadas , Células Clonais , Técnicas de Cocultura , Células Dendríticas/metabolismo , Regulação para Baixo/imunologia , Indução Enzimática/imunologia , Soros Imunes/farmacologia , Imunossupressores/imunologia , Interferon gama/antagonistas & inibidores , Interferon gama/farmacologia , Interleucina-6/biossíntese , Interleucina-6/imunologia , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Receptores de Interferon/antagonistas & inibidores , Receptores de Interferon/biossíntese , Linfócitos T/citologia , Linfócitos T/imunologia , Triptofano Oxigenase/antagonistas & inibidores , Receptor de Interferon gamaRESUMO
Similar to myeloid dendritic cells, murine macrophages and macrophage cell lines were found to express a surface receptor for IL-12. As a result, peritoneal macrophages could be primed by IL-12 to present an otherwise poorly immunogenic tumor peptide in vivo. Using binding analysis and RNase protection assay, we detected a single class of high affinity IL-12 binding sites (K(d) of approximately 35 pM) whose number per cell was increased by IFN-gamma via up-regulation of receptor subunit expression. Autocrine production of IL-12 was suggested to be a major effect of IL-12 on macrophages when the cytokine was tested alone or after priming with IFN-gamma in vitro. In vivo, combined treatment of macrophages with IFN-gamma and IL-12 resulted in synergistic effects on tumor peptide presentation. Therefore, our findings suggest a general and critical role of IL-12 in potentiating the accessory function of myeloid APC.
Assuntos
Interferon gama/fisiologia , Interleucina-12/fisiologia , Macrófagos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/fisiologia , Sequência de Aminoácidos , Animais , Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Sinergismo Farmacológico , Feminino , Interferon gama/administração & dosagem , Interleucina-12/administração & dosagem , Interleucina-12/biossíntese , Interleucina-12/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Dados de Sequência Molecular , Oligopeptídeos/administração & dosagem , Oligopeptídeos/síntese química , Oligopeptídeos/imunologia , Ligação Proteica/imunologia , Receptores de Interleucina/biossíntese , Receptores de Interleucina-12 , Fator de Transcrição STAT3 , Fator de Transcrição STAT4 , Transdução de Sinais/imunologia , Transativadores/metabolismo , Células Tumorais CultivadasAssuntos
Desenho de Fármacos , Imunoterapia , Animais , Autoimunidade/imunologia , Controle de Doenças Transmissíveis , Doenças Transmissíveis/imunologia , Humanos , Hipersensibilidade/terapia , Sistema Imunitário/imunologia , Imunidade Ativa/imunologia , Imunidade Inata/imunologia , Imunoterapia/métodos , Neoplasias/terapia , VacinaçãoRESUMO
The outcome of dendritic cell (DC) presentation of P815AB, a tolerogenic tumor/self peptide, depends on a balance between the respective immunogenic and tolerogenic properties of myeloid (CD8 alpha(-)) and lymphoid (CD8 alpha(+)) DC. We have previously shown that CD8(-) DC can be primed by IL-12 to overcome inhibition by the CD8(+) subset and initiate immunogenic presentation in vivo when the two types of peptide-pulsed DC are cotransferred into recipient hosts. IFN-gamma enhances the inhibitory activity of CD8(+) DC on Ag presentation by the other subset, blocking the ability of IL-12-treated CD8(-) DC to overcome suppression. We report here that CD40 ligation on lymphoid DC ablated their inhibitory function on Ag presentation as well as IFN-gamma potentiation of the effect. CD40 modulation of IFN-gamma action on lymphoid DC involved a reduction in IFN-gamma R expression and tryptophan-degrading ability. This effect was accompanied in vitro by an impaired capacity of the CD40-modulated and IFN-gamma-treated DC to initiate T cell apoptosis. In vivo, not only did CD40 triggering on lymphoid DC abrogate their tolerogenic activity, but it also induced the potential for immunogenic presentation of P815AB. Importantly, a pattern similar to P815AB as well as CD40 modulation of lymphoid DC function were observed on testing reactivity to NRP, a synthetic peptide mimotope recognized by diabetogenic CD8(+) T cells in nonobese diabetic mice.
Assuntos
Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Baço/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Apresentação de Antígeno , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Apoptose/imunologia , Antígenos CD40/fisiologia , Antígenos CD8/biossíntese , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Diabetes Mellitus Tipo 1/imunologia , Regulação para Baixo/imunologia , Indução Enzimática/imunologia , Interferon gama/antagonistas & inibidores , Interferon gama/metabolismo , Interferon gama/farmacologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos DBA , Camundongos Endogâmicos NOD , Mimetismo Molecular/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Receptores de Interferon/antagonistas & inibidores , Receptores de Interferon/biossíntese , Baço/citologia , Baço/metabolismo , Linfócitos T/citologia , Linfócitos T/enzimologia , Linfócitos T/imunologia , Triptofano Oxigenase/antagonistas & inibidores , Triptofano Oxigenase/biossíntese , Receptor de Interferon gamaRESUMO
Although CD8(+) T cells play a central role as immune effectors, CD4(+) T cells act to control the activation and persistence of the CD8(+) T cell response in autoimmune disease, antiviral immunity, and experimental systems with immunogenic model tumor Ag. However, little information is available on the effects of CD4(+) T cells on the function of endogenous CD8(+) T lymphocytes recognizing authentic tumor rejection Ag with limited immunogenicity. We report here that the prophylactic or postchallenge administration of T helper Th1-type and Th2-type CD4(+) clones specific for an unmutated rejection Ag (murine P815AB, resembling tumor-specific shared Ag in humans) leads to the induction of P815AB-specific reactivity in vivo and concomitant tumor destruction, with quantitative rather than qualitative differences characterizing the antitumor activity of Th1 vs Th2 cells. Because the transferred CD4(+) cells lacked direct antitumor activity in vitro and required the de novo generation of P815AB-specific CD8(+) T cells in vivo, these findings suggest that CD4(+) lymphocytes can enhance the ability of host APC to initiate an endogenous CD8(+) T cell response to authentic, poorly immunogenic tumor rejection Ag.
Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva , Sarcoma Experimental/imunologia , Sarcoma Experimental/terapia , Células Th1/transplante , Células Th2/transplante , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Células Clonais/imunologia , Células Clonais/transplante , Relação Dose-Resposta Imunológica , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/imunologia , Imunoterapia Adotiva/métodos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos DBA , Dados de Sequência Molecular , Transplante de Neoplasias , Oligopeptídeos/síntese química , Oligopeptídeos/imunologia , Sarcoma Experimental/prevenção & controle , Células Th1/imunologia , Células Th2/imunologia , Células Tumorais CultivadasRESUMO
Using an in vivo model of tumor/self peptide presentation for induction of class I-restricted skin test reactivity, we have previously shown that a minority population of CD8+ dendritic cells (DC) negatively regulates the induction of T cell reactivity by peptide-loaded CD8- DC in DBA/2 mice. However, the CD8- fraction can be primed by IL-12 to overcome inhibition by the CD8+ subset when the two types of DC are cotransferred into recipient hosts. We report here that exposure of CD8+ DC to IFN-gamma greatly enhances their inhibitory activity on Ag presentation by the other subset, blocking the ability of IL-12-treated CD8- DC to overcome suppression. In contrast, IFN-gamma has no direct effects on the APC function of the latter cells and does not interfere with IL-12 signaling. The negative regulatory effect triggered by IFN-gamma in CD8+ DC appears to involve interference with tryptophan metabolism in vivo. Through tryptophan depletion affecting T cell responses, IFN-gamma acting on CD8+ DC may thus contribute to regulation of immunity to tumor/self peptides presented by the CD8- subset.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/metabolismo , Antígenos CD8/biossíntese , Células Dendríticas/metabolismo , Imunossupressores/farmacologia , Interferon gama/farmacologia , Peptídeos/imunologia , Adjuvantes Imunológicos/antagonistas & inibidores , Adjuvantes Imunológicos/farmacologia , Animais , Antígenos de Neoplasias/imunologia , Separação Celular , Células Cultivadas , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Sinergismo Farmacológico , Indução Enzimática/imunologia , Vírus da Influenza A/imunologia , Injeções Intravenosas , Interleucina-12/antagonistas & inibidores , Interleucina-12/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Nucleoproteínas/imunologia , Fragmentos de Peptídeos/imunologia , Peptídeos/antagonistas & inibidores , Peptídeos/metabolismo , Triptofano Oxigenase/biossíntese , Proteínas do Core Viral/imunologiaRESUMO
We assessed the effect of rIL-12 on the expression of class II molecules and on the ratio between SDS-stable and unstable alphabeta dimers in dendritic cells. We found that in vitro exposure of the cells to IL-12 increased their surface expression of mature class II molecules, despite a marked decline in class II biosynthesis. This effect was accompanied by a striking increase in the overall proportion of SDS-stable heterodimers.
Assuntos
Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe II/biossíntese , Interleucina-12/imunologia , Dodecilsulfato de Sódio , Animais , Western Blotting/métodos , Células Dendríticas/efeitos dos fármacos , Dimerização , Interleucina-12/farmacologia , Camundongos , Camundongos Endogâmicos DBARESUMO
To determine the effect of interleukin 4 (IL-4) administration in a live sepsis model characterised by high-level production of tumour necrosis factor a (TNF-alpha), mice infected systemically with lethal or sublethal inocula of Pseudomonas aeruginosa were given the recombinant cytokine at different times before infection. Improved survival and decreased TNF-alpha production were observed in lethally infected mice treated with the cytokine 1 day before challenge. In contrast, increased mortality and overproduction of TNF-alpha were observed in sublethally infected mice given IL-4 at the time of infection.
Assuntos
Interleucina-4/imunologia , Infecções por Pseudomonas/imunologia , Sepse/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Células Cultivadas , Modelos Animais de Doenças , Interleucina-12/imunologia , Interleucina-12/farmacologia , Interleucina-4/administração & dosagem , Interleucina-4/metabolismo , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Sepse/prevenção & controleRESUMO
IL-9 is a T cell-derived cytokine that, similar to the Th2 cytokines IL-4 and IL-10, has been implicated in the response to parasitic infections, allergy, and inflammatory processes. Because both IL-4 and IL-10 can confer protection to mice from septic shock, we investigated whether IL-9 may also be capable of conferring resistance on recipients of an otherwise lethal challenge with Pseudomonas aeruginosa. Prophylactic injections of rIL-9 appeared to be most effective in preventing the onset of a lethal shock, according to a pattern that was both dose dependent and time dependent. The protective effect of IL-9 was correlated with marked decreases in the production of the inflammatory mediators TNF-alpha, IL-12, and IFN-gamma, as well as the induction of the anti-inflammatory cytokine IL-10. Sustained levels of IL-9-specific transcripts could be detected in the spleens of mice recovering from sublethal P. aeruginosa infection. Therefore, IL-9 may be protective in septic shock via a rather unique mechanism involving a complex modulation of inflammatory and anti-inflammatory mediators.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Interferon gama/antagonistas & inibidores , Interleucina-10/biossíntese , Interleucina-12/antagonistas & inibidores , Interleucina-9/uso terapêutico , Infecções por Pseudomonas/prevenção & controle , Choque Séptico/prevenção & controle , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/genética , Animais , Anticorpos Monoclonais/farmacologia , Quimioterapia Combinada , Feminino , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Injeções Intraperitoneais , Interferon gama/biossíntese , Interleucina-10/antagonistas & inibidores , Interleucina-10/imunologia , Interleucina-12/biossíntese , Interleucina-9/administração & dosagem , Interleucina-9/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Pentoxifilina/administração & dosagem , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/imunologia , RNA Mensageiro/biossíntese , Choque Séptico/imunologia , Choque Séptico/metabolismo , Choque Séptico/patologia , Baço/imunologia , Baço/metabolismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Previous work has shown that a significant proportion of murine splenic dendritic cells (DC) express a high affinity receptor for IL-12, thus accounting for the adjuvanticity of the cytokine when DBA/2 mice are transferred with syngeneic DC exposed in vitro to rIL-12 and an otherwise poorly immunogenic tumor peptide. In DBA/2 mice, splenic DC consist of 90-95% CD8- and 5-10% CD8+ cells. To detect any difference in IL-12 responsiveness among phenotypically distinct DC subtypes, enriched CD8- (>99% pure) and CD8+ ( approximately 80% pure) populations of DC from DBA/2 spleens were assayed for APC function in vivo following exposure to rIL-12 and tumor peptide in vitro. Unlike unfractionated DC, the CD8- fraction was capable of effective presentation of the peptide even when the cells had not been pretreated with IL-12 before peptide pulsing. The addition of as few as 3% CD8+ cells during pulsing blocked in vivo priming by the CD8- fraction. However, pretreatment of CD8- DC with IL-12 before cell mixing and peptide pulsing ablated the inhibitory effect of the CD8+ fraction. CD8-, but not CD8+, DC showed significant message expression for the beta 1 and beta 2 subunits of the IL-12 receptor. These data suggest that a minority population of CD8+ DC, which appeared to secrete IL-10 in vitro, negatively regulates the induction of T cell reactivity by peptide-loaded CD8- DC in DBA/2 mice. However, the CD8- fraction can be primed by IL-12 to overcome the inhibitory effect of the CD8+ subtype.