RESUMO
The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ-independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, l-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Transplante de Células-Tronco Hematopoéticas , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Pneumonia/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Feminino , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/mortalidade , Inibidores de Histona Desacetilases/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Interferon gama/genética , Interferon gama/metabolismo , Interferon gama/farmacologia , Cinurenina/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Pneumonia/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Tacrolimo/farmacologia , Receptor de Interferon gamaRESUMO
A long-standing question in the field of tumor immunotherapy is how Th2 cytokines block tumor growth. Their antitumor effects are particularly prominent when they are secreted continuously in tumors, suggesting that Th2 cytokines may create a tumor microenvironment unfavorable for tumor growth independently of adaptive immunity. In this study, we show that local production of IL-33 establishes a high number of type 2 innate lymphoid cells (ILC2s) with potent antitumor activity. IL-33 promotes secretion of a massive amount of CXCR2 ligands from ILC2s but creates a tumor microenvironment where tumor cells express CXCR2 through a dysfunctional angiogenesis/hypoxia/reactive oxygen species axis. These two signaling events converge to reinforce tumor cell-specific apoptosis through CXCR2. Our results identify a previously unrecognized antitumor therapeutic pathway wherein ILC2s play a central role.
Assuntos
Imunidade Inata , Linfócitos do Interstício Tumoral/imunologia , Linfócitos/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Animais , Antígenos de Superfície/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hipóxia/metabolismo , Imunofenotipagem , Interleucina-33/metabolismo , Linfócitos/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais , Carga Tumoral , Microambiente TumoralRESUMO
Susceptibility to systemic Candida albicans infection is determined by immune resistance, as well as by the ability to control Candida-induced immunopathologies. We showed previously that exogenous IL-33 can increase resistance to peritoneal C. albicans infection by regulating multiple steps of the neutrophil anti-Candida response. In this study, using a mouse model of systemic candidiasis, we observed that IL-33 administration limited fungal burden and inflammation and increased survival. In kidneys, IL-33 seemed to directly act on neutrophils and CD4(+) T cells: IL-33 administration enhanced fungal clearance by increasing neutrophil phagocytic activity without which Candida proliferation was uncontrollable. In contrast, IL-33 stimulated CD4(+) T cells to produce IL-13, which, in turn, drove the polarization of macrophages toward the M2 type. Furthermore, the absence of IL-13 abolished IL-33-mediated polarization of M2 macrophages and renal functional recovery. In addition, IL-33 and IL-13 acted synergistically to increase M2 macrophage polarization and its phagocytic activity. Overall, this study identifies IL-33 as a cytokine that is able to induce resistance and tolerance and suggests that targeting resistance and tolerance simultaneously with therapeutic IL-33 may benefit patients with systemic candidiasis.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Candida albicans/imunologia , Candidíase/imunologia , Tolerância Imunológica/imunologia , Interleucina-13/imunologia , Interleucinas/imunologia , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Interleucina-13/biossíntese , Interleucina-33 , Nefropatias/imunologia , Nefropatias/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo RealRESUMO
IL-33 has been implicated in the pathogenesis of asthma, atopic allergy, anaphylaxis, and other inflammatory diseases by promoting the production of proinflammatory cytokines and chemokines or Th2 immune responses. In this study, we analyzed the in vivo effect of IL-33 administration. IL-33 markedly promoted myelopoiesis in the bone marrow and myeloid cell emigration. Concomitantly, IL-33 induced hematopoietic stem and progenitor cell (HSPC) mobilization and extramedullary hematopoiesis. HSPC mobilization was mediated mainly through increased levels of CCL7 produced by vascular endothelial cells in response to IL-33. In vivo treatment of IL-33 rapidly induced phosphorylation of ERK, JNK, and p38, and inhibition of these signaling molecules completely blocked the production of CCL7 induced by IL-33. Consistently, inhibitor of CCR2 markedly reduced IL-33-mediated HSPC mobilization in vivo and migration of HSPCs in response to CCL7 in vitro. IL-33-mobilized HSPCs were capable of homing to, and of long-term reconstitution in, the bone marrow of irradiated recipients. Immune cells derived from these recipients had normal antifungal activity. The ability of IL-33 to promote migration of HSPCs and myeloid cells into the periphery and to regulate their antifungal activity represents a previously unrecognized role of IL-33 in innate immunity. These properties of IL-33 have clinical implications in hematopoietic stem cell transplantation.
Assuntos
Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Interleucinas/farmacologia , Células Mieloides/imunologia , Mielopoese/imunologia , Receptores CCR2/imunologia , Animais , Autoenxertos , Transplante de Medula Óssea , Quimiocina CCL7/genética , Quimiocina CCL7/imunologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Feminino , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Interleucina-33 , Interleucinas/genética , Interleucinas/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mielopoese/efeitos dos fármacos , Receptores CCR2/genéticaRESUMO
IL-33 is known to play an important role in Th2 immunity. In this study, we investigated the effect of IL-33 pretreatment on anti-fungal response using an acute Candida albicans peritoneal infection model. IL-33 pretreatment induced a rapid fungal clearance and markedly reduced the C. albicans infection-associated mortality. The priming effect of IL-33 occurred during multiple steps of the neutrophil-mediated anti-fungal response. First, the anti-fungal effect occurred due to the rapid and massive recruitment of neutrophils to the site of infection as a result of the release of CXCR2 chemokines by peritoneal macrophages and by reversal of the TLR-induced reduction of CXCR2 expression in neutrophils during IL-33 priming. Second, conditioning of neutrophils by IL-33 activated the TLR and dectin-1 signaling pathways, leading to the upregulation of complement receptor 3 expression induced by C. albicans. Upregulated CR3 in turn increased the phagocytosis of opsonized C. albicans and resulted in the production of high levels of reactive oxygen species and the subsequent enhanced killing activity of neutrophils. Taken together, our results suggest that IL-33 can regulate the anti-fungal activity of neutrophils by collaborative modulation of the signaling pathways of different classes of innate immune receptors.
Assuntos
Candida albicans/imunologia , Interleucinas/fisiologia , Lectinas Tipo C/fisiologia , Neutrófilos/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo , Animais , Antígeno CD11b/biossíntese , Candida albicans/crescimento & desenvolvimento , Candidíase/metabolismo , Candidíase/patologia , Candidíase/prevenção & controle , Movimento Celular/imunologia , Feminino , Interleucina-33 , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/microbiologia , Neutrófilos/patologia , Fagocitose/imunologia , Receptores Toll-Like/fisiologia , Regulação para Cima/imunologiaRESUMO
Microplastics (MPs) are ubiquitous in the environment, posing a threat to ecosystems and causing increasing concerns regarding their impacts on the human body through exposure. However, there has been limited research on the presence of MPs in functional foods, despite them being consumed for health improvement. This study aimed to investigate MP occurrence in various omega-3 oils and oil products in the Korean market and its relation to the source of raw material or manufacture. MPs were investigated in omega-3 capsules and raw oil, sourced from both plant-based (PB) and animal-based (AB) sources. We developed a method of direct filtration with acetone washing for collecting and characterizing MPs larger than 5 µm using micro-Raman spectroscopy. The average number of MPs by mass was found to be 1.2 ± 1.7 MPs/g for PB raw oil, 2.2 ± 1.7 MPs/g for AB raw oil, 3.5 ± 3.9 MPs/g for PB capsule oil, and 10.6 ± 8.9 MPs/g for AB capsule oil. Polypropylene and polyethylene terephthalate were the major MP species (83-95%) found in omega-3 oil. The proportions based on size range remained consistent across all groups, with a trend of being detected at higher rates as the size decreased. The results reveal that the main reason for the MP contamination of omega-3 oil is not the source of raw material but the manufacturing and packaging process.
RESUMO
KEY POINTS: Microplastics were identified in nasal irrigations Polypropylenes, which were the main component of the nozzle, were commonly identified Additional studies are needed to understand the biological relevance of microplastics in nasal irrigations.
Assuntos
Microplásticos , Rinite , Humanos , Plásticos , Lavagem Nasal , Líquido da Lavagem Nasal , Doença Crônica , Irrigação TerapêuticaRESUMO
Evidence of microplastics in humans has recently been demonstrated. The primary route of human exposure to microplastics is consumption of contaminated food and water. However, quantitative estimations of exposure to microplastics are limited, which hinders human health risk assessments. In this study, abundances of microplastics were measured in eight food types, comprising 90 products of table salts, soy sauces, fish sauces, salted seafood, seaweed, honey, beer, and beverage. Aggregate human exposure to microplastics via food consumption was assessed based on the number and mass of microplastics, using deterministic calculations and Monte Carlo simulations. The determinations revealed that average adult Koreans likely ingest 1.4 × 10-4 and 3.1 × 10-4 g of microplastics per week, respectively. These results are orders of magnitude smaller than earlier estimates of 0.1-5 g of microplastics per week that likely chose experimental outliers. Therefore, careful selection of literature data and estimation methods is needed to provide more realistic exposure estimations from microplastic counts. This study extends our understanding of MP occurrence in food and provides a more thorough estimate of aggregate microplastic exposure via food consumption.
Assuntos
Microplásticos , Poluentes Químicos da Água , Animais , Humanos , Plásticos , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Alimentos Marinhos/análise , República da CoreiaRESUMO
Microplastics (< 5 mm) have been found in marine ecosystems worldwide, even in Antarctic ecosystems. In this study, the stomach and upper intestines of 14 dead gentoo penguin (Pygoscelis papua) chicks were collected and screened for microplastics on King George Island, a gateway to Antarctic research and tourism. A total of 378 microplastics were identified by Fourier-transform infrared spectroscopy, with 27.0 ± 25.3 microplastics per individual. The detected number of microplastics did not increase with the mass of penguin chicks, suggesting no permanent accumulation of microplastics. However, the concentration of microplastics was much higher (9.1 ± 10.8 microplastics per individual within the size range 100-5000 µm) than the previously reported concentration in the penguin feces, and a greater number of smaller microplastics were found. Marine debris surveys near the breeding colony found various plastic (79.3%) to be the most frequent type of beached debris, suggesting that local sources of marine plastic waste could have contributed to microplastic contamination of penguin chicks being fed by parents that forage in nearby seas. This finding confirms the presence of microplastics in an Antarctic ecosystem and suggests the need for stronger waste management in Antarctica and a standardized scheme of microplastic monitoring in this once-pristine ecosystem.
Assuntos
Spheniscidae , Animais , Microplásticos , Plásticos , Ecossistema , Regiões Antárticas , Galinhas , Trato Gastrointestinal , Monitoramento AmbientalRESUMO
Large amounts of microplastics are discharged into wastewater treatment plants (WWTPs), from where some of them are released into natural waterbodies on account of their not being fully eliminated by WWTPs. To investigate the behavior and emission of microplastics from WWTPs, we selected four WWTPs with different treatment technologies, including anaerobic-anoxic-aerobic (A2O), sequence batch reactor (SBR), media, and membrane bioreactor (MBR). The number of microplastics detected using Fourier transform infrared (FT-IR) spectroscopy ranged from 520 to 1820 particles/L in influent and from 0.56 to 2.34 particles/L in effluent. The microplastic removal efficiencies of four WWTPs were over 99%, indicating that the type of treatment technologies did not significantly affect the removal rate of microplastics. In the unit process for each WWTP, the major stages relating to microplastic removal were the secondary clarifier and tertiary treatment processes. Most microplastics detected were categorized as fragments and fibers, while other types were hardly detected. The size of more than 80% of microplastic particles detected in WWTPs ranged between 20 and 300 µm, indicating that they were significantly smaller than the size threshold defined for microplastics. Therefore, we used thermal extraction-desorption coupled with gas chromatography-mass spectroscopy (TED-GC-MS) to evaluate the microplastic mass content in all four WWTPs, and the results were compared with those of the FT-IR analysis. In this method, only four components, namely polyethylene, polypropylene, polystyrene, and polyethylene terephthalate, were analyzed because of the analysis limitation, and the total microplastic concentration represented the sum of four components concentrations. The influent and effluent microplastic concentrations estimated by TED-GC-MS ranged from not detectable to 160 µg/L and 0.04-1.07 µg/L, respectively, indicating a correlation coefficient of 0.861 (p < 0.05) between the TED-GC-MS and FT-IR results, when compared to the combined abundance of the four microplastic components by FT-IR analysis.
Assuntos
Poluentes Químicos da Água , Purificação da Água , Microplásticos , Plásticos/análise , Águas Residuárias , Espectroscopia de Infravermelho com Transformada de Fourier , Análise de Fourier , Cromatografia Gasosa-Espectrometria de Massas , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Eliminação de Resíduos LíquidosRESUMO
CD25(+)CD4(+)Foxp3(+) regulatory T cells (Tregs) play a pivotal role in the maintenance of self-tolerance and regulation of immune responses. Previous studies have demonstrated that CD137 signals can promote proliferation and survival of Tregs in vitro. Here, we show that in vivo CD137-induced expansion of Tregs in naive mice was dependent upon IL-2 secreted by memory T cells. Tregs primed by anti-CD137 mAbs had a higher immunosuppressive capacity. Preconditioning with anti-CD137 mAbs significantly inhibited graft-versus-host disease (GVHD) in the C57BL/6 â (C57BL/6 × DBA/2) F1 acute GVHD model. In this disease model, a high proportion of host Tregs remained long-term in the recipient spleen, whereas donor hematopoietic cells replaced other host bone marrow-derived cells. Transient depletion of Tregs before transfer of donor cells completely abrogated the inhibitory effect of anti-CD137 mAbs on GVHD. In addition, adoptive transfer of anti-CD137-primed Tregs ameliorated GVHD. Our results demonstrate that it is possible to enhance the survival and/or the immunosuppressive activity of host Tregs in nonmyeloablative GVHD, and that 1 way of accomplishing this is through the prophylactic use of anti-CD137 mAbs in nonmyeloablative GVHD.
Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD4/imunologia , Fatores de Transcrição Forkhead/imunologia , Doença Enxerto-Hospedeiro/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Anticorpos Monoclonais/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genéticaRESUMO
The accumulation of microplastics in marine organisms is an emerging concern. Due to trophic transfer, the safety of seafood is under investigation in view of the potential negative effects of microplastics on human health. In this study, market samples of Manila clams (Ruditapes philippinarum) from South Korea were segregated into two groups of considerably different size (p < 0.05), namely small clams with shell length of 40.69 ± 3.97 mm, and large clams of shell length 51.19 ± 2.86 mm. Comparative profiling of the number, size, shape, and polymer type of microplastics were performed using µFTIR imaging and Nile red staining. Overall, µFTIR detected only 1559 microplastics while 1996 microplastics were counted based on staining from 61 Manila clams (30 small and 31 large), leading to an overestimation of 18 to 75 %. Comparable microplastics concentration, based on µFTIR, were observed at 2.70 ± 1.66 MP/g or 15.64 ± 9.25 MP/individual for the small samples, and 3.65 ± 1.59 MP/g or 41.63 ± 16.90 MP/individual for the large ones (p > 0.05). Particle diameters of 20-100 µm was the most dominant, accounting for 44.6 % and 46.5 % of all microplastics from the small and large groups, respectively. Particles, with a circularity (resemblance to a circle) value between 0.6 and 1.0, were the most prevalent, followed by fragments and fibers. At least 50 % of microplastics from the small and large samples were polystyrene, making it the most abundant polymer type. Despite the substantial difference in the size of the animals, only a weak to moderate correlation was observed between microplastics content and the physical attributes of the clams such as shell length and weight, (soft) tissue weight, and total weight (Spearman's coefficient < 0.5). The estimated intake of microplastics by the Korean population was 1232 MP/person/year via small clams, 1663 MP/person/year via large clams, and 1489 MP/person/year via clams independent of size.
Assuntos
Bivalves , Poluentes Químicos da Água , Animais , Humanos , Microplásticos , Oxazinas , Plásticos/farmacologia , República da Coreia , Coloração e Rotulagem , Poluentes Químicos da Água/análiseRESUMO
In the DBA/2 --> unirradiated (C57BL/6 x DBA/2)F(1) model of chronic graft-vs-host disease (cGVHD), donor CD4(+) T cells play a critical role in breaking host B cell tolerance, while donor CD8(+) T cells are rapidly removed and the remaining cells fall into anergy. Previously we have demonstrated that in vivo ligation of GITR (glucocorticoid-induced TNF receptor-related gene) can activate donor CD8(+) T cells, subsequently converting the disease pattern from cGVHD to an acute form. In this study, we investigated the effect of an agonistic mAb against CD40 on cGVHD. Treatment of anti-CD40 mAb inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis. The inhibition of cGVHD occurred because anti-CD40 mAb prevented donor CD8(+) T cell anergy such that subsequently activated donor CD8(+) T cells deleted host CD4(+) T cells and host B cells involved in autoantibody production. Additionally, functionally activated donor CD8(+) T cells induced full engraftment of donor hematopoietic cells and exhibited an increased graft-vs-leukemia effect. However, induction of acute GVHD by donor CD8(+) T cells seemed to be not so apparent. Further CTL analysis indicated that there were lower levels of donor CTL activity against host cells in mice that received anti-CD40 mAb, compared with mice that received anti-GITR mAb. Taken together, our results suggest that a different intensity of donor CTL activity is required for removal of host hematopoietic cells, including leukemia vs induction of acute GVHD.
Assuntos
Antígenos CD40/antagonistas & inibidores , Linfócitos T CD8-Positivos/imunologia , Anergia Clonal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais/imunologia , Autoantígenos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Citotoxicidade Imunológica , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Efeito Enxerto vs Leucemia/imunologia , Imuno-Histoquímica , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
C-C chemokine receptor type 5 (CCR5) regulates the trafficking of various immune cells to sites of infection. In this study, we showed that expression of CCR5 and its ligands was rapidly increased in the kidney after systemic Candida albicans infection, and infected CCR5-/- mice exhibited increased mortality and morbidity, indicating that CCR5 contributes to an effective defense mechanism against systemic C. albicans infection. The susceptibility of CCR5-/- mice to C. albicans infection was due to impaired fungal clearance, which in turn resulted in exacerbated renal inflammation and damage. CCR5-mediated recruitment of NK cells to the kidney in response to C. albicans infection was necessary for the anti-microbial activity of neutrophils, the main fungicidal effector cells. Mechanistically, C. albicans induced expression of IL-23 by CD11c+ dendritic cells (DCs). IL-23 in turn augmented the fungicidal activity of neutrophils through GM-CSF production by NK cells. As GM-CSF potentiated production of IL-23 in response to C. albicans, a positive feedback loop formed between NK cells and DCs seemed to function as an amplification point for host defense. Taken together, our results suggest that CCR5-mediated recruitment of NK cells to the site of fungal infection is an important step that underlies innate resistance to systemic C. albicans infection.
RESUMO
Human exposure to microplastics contained in food has become a significant concern owing to the increasing accumulation of microplastics in the environment. In this paper, we summarize the presence of microplastics in food and the analytical methods used for isolation and identification of microplastics. Although a large number of studies on seafood such as fish and shellfish exist, estimating the overall human exposure to microplastics via food consumption is difficult owing to the lack of studies on other food items. Analytical methods still need to be optimized for appropriate recovery of microplastics in various food matrices, rendering a quantitative comparison of different studies challenging. In addition, microplastics could be added or removed from ingredients during processing or cooking. Thus, research on processed food is crucial to estimate the contribution of food to overall human microplastic consumption and to mitigate this exposure in the future.
Assuntos
Plásticos , Poluentes Químicos da Água , Animais , Monitoramento Ambiental , Humanos , Microplásticos , Alimentos Marinhos/análise , Espectroscopia de Infravermelho com Transformada de Fourier , Poluentes Químicos da Água/análiseRESUMO
CD137, a potent costimulatory receptor for CD8+ T cells, is expressed in various non-T cells, but little is known about its regulatory functions in these cells. In this study, we show that CD137 signaling, specifically in intestinal CD11b-CD103+ dendritic cells (DCs), restricts acute colitis progression. Mechanistically, CD137 engagement activates TAK1 and subsequently stimulates the AMPK-PGC-1α axis to enhance expression of the Aldh1a2 gene encoding the retinoic acid (RA) metabolizing enzyme RALDH2. RA can act on CD11b+CD103- DCs and induce SOCS3 expression, which, in turn, suppresses p38MAPK activation and interleukin-23 (IL-23) production. Administration of RA in DC-specific CD137-/- mice represses IL-23-producing CD11b+CD103- DCs and TH17 cells, indicating that RA is a major inhibitory effector molecule against intestinal CD11b+CD103- DCs. Additionally, the therapeutic effect of the anti-CD137 antibody is abrogated in DC-specific CD137-/- mice. Taken together, our results define a mechanism of paracrine immunoregulation operating between adjacent DC subsets in the intestine.
Assuntos
Aldeído Oxirredutases/metabolismo , Antígenos CD/metabolismo , Antígeno CD11b/metabolismo , Colite/patologia , Células Dendríticas/metabolismo , Cadeias alfa de Integrinas/metabolismo , Transdução de Sinais , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Doença Aguda , Adenilato Quinase/metabolismo , Animais , Apoptose , Diferenciação Celular , Colite/imunologia , Suscetibilidade a Doenças , Fatores de Transcrição Forkhead/metabolismo , Intestinos/patologia , MAP Quinase Quinase Quinases/metabolismo , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/citologia , Tretinoína/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiênciaRESUMO
Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. We previously showed that anti-CD137 monoclonal antibody (mAb) can cure advanced cGVHD by inducing activation-induced cell death of donor T cells. In this study, we examined whether administration of anti-CD137 mAb can prevent the development of cGVHD after bone marrow transplantation (BMT) in mice conditioned with total body irradiation (TBI). We used the B10.D2-->Balb/c (H-2(d)) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD. A single injection of anti-CD137 mAb was administered immediately after BMT. In contrast to the results obtained from the curing model of cGVHD, anti-CD137 given simultaneously with BMT resulted in lethal GVHD. Histopathologic evaluation revealed inflammation and damage of target organs from acute GVHD (aGVHD) in anti-CD137-treated mice. Anti-CD137-induced lethal aGVHD required host cells, as well as irradiation and mature donor T cells. Apparently, anti-CD137 mAb rapidly induced activation of donor T cells and sustained their activation status under the inflammatory condition triggered by irradiation. When given on day 12 after irradiation and BMT, anti-CD137 mAb could still exacerbate GVHD, but when given on day 30, it could not. Our data demonstrate that anti-CD137 mAb can amplify inflammation induced by host preconditioning, subsequently resulting in lethal aGVHD; thus, alleviating irradiation-induced toxicity is critical to allow the use of anti-CD137 mAb as GVHD prophylaxis.
Assuntos
Anticorpos Monoclonais/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Doença Aguda , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Doença Enxerto-Hospedeiro/patologia , Tolerância Imunológica , Inflamação/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Intestino Grosso/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Células-Tronco/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Irradiação Corporal TotalRESUMO
CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137-/- mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL12-producing CD103+ DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFNγ-producing CD8+ cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL12 and IFNγ, which promoted intratumoral differentiation of IFNγ-producing Tc1, IL12-producing CD103+ DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward-feedback loop for activation of CD103+ DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance. Cancer Res; 77(21); 5989-6000. ©2017 AACR.
Assuntos
Ligante 4-1BB/imunologia , Anticorpos Monoclonais/farmacologia , Neoplasias/imunologia , Transdução de Sinais/efeitos dos fármacos , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Ligante 4-1BB/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
GITR (glucocorticoid-induced TNF receptor) is a recently identified member of the TNF receptor superfamily. The receptor is preferentially expressed on CD4+CD25+ regulatory T cells and GITR signals break the suppressive activity of the subset. In this study, we wanted to reveal the in vivo function of GITR in chronic graft-versus-host disease (cGVHD), a lupus-like autoimmune disease. A single injection of anti-GITR monoclonal antibody (DTA-1) was effective in blocking the progression of cGVHD in the parent-into-F1 model. Treatment of DTA-1 significantly decreased levels of IgG1 anti-DNA autoantibody, inhibited glomerulonephritis, and increased survival. The DTA-1-mediated inhibition of autoantibody production correlated with deletion of B cells and could occur independently of CD4+CD25+ regulatory T cells. Our results indicate that anti-GITR monoclonal antibody may be used as a potential immunotherapeutic agent for preventing cGVHD.
Assuntos
Glucocorticoides/farmacologia , Doença Enxerto-Hospedeiro/prevenção & controle , Receptores do Fator de Necrose Tumoral/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Fluoresceína-5-Isotiocianato , Técnica Indireta de Fluorescência para Anticorpo , Corantes Fluorescentes , Camundongos , Camundongos Endogâmicos DBA , Camundongos Endogâmicos , Microscopia Confocal , Transplante HomólogoRESUMO
In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8+ T cells rapidly fall into anergy to host cells, while donor CD4+ T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8+ T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8+ T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4+CD25+ regulatory T cells (Treg cells) are critical in maintaining the donor CD8+ T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of Treg cells in determining cGVHD versus aGVHD.