RESUMO
Although the cytokine interleukin 9 (IL-9) was discovered decades ago, it remains one of the most enigmatic cytokines identified so far, in particular because its functional activities remain far from clear. Breakthroughs made through the use of IL-9 reporter mice have allowed the identification of cell types that produce IL-9 in vivo and, contrary to expectations based on previous results obtained in vitro, it is not T cells but instead a previously unknown type of innate lymphoid cell, called the 'ILC2 cell', that is the main cell type that expresses IL-9 in vivo. In this perspective, we put forward a hypothesis about the potential biological functions of IL-9 in the immune system and beyond.
Assuntos
Interleucina-9/imunologia , Células Th2/imunologia , Animais , Sobrevivência Celular/imunologia , Humanos , CamundongosRESUMO
Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) experienced paralysis and lost weight at a greater rate than mice who had previously been infected with LDV. LDV infection decreased the presentation of the MOG peptide by CD11b+CD11c+ dendritic cells (DC) to pathogenic T lymphocytes. When comparing non-infected mice to infected mice, the histopathological examination of the CNS showed more areas of demyelination and CD45+ and CD3+, but not Iba1+ cell infiltration. These results suggest that the protective effect of LDV infection against EAE development is mediated by a suppression of myelin antigen presentation by a specific DC subset to autoreactive T lymphocytes. Such a mechanism might contribute to the general suppressive effect of infections on autoimmune diseases known as the hygiene hypothesis.
Assuntos
Células Dendríticas , Encefalomielite Autoimune Experimental , Vírus Elevador do Lactato Desidrogenase , Esclerose Múltipla , Glicoproteína Mielina-Oligodendrócito , Animais , Feminino , Camundongos , Apresentação de Antígeno/imunologia , Infecções por Cardiovirus/imunologia , Antígeno CD11b/metabolismo , Antígeno CD11b/imunologia , Antígeno CD11c/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/virologia , Vírus Elevador do Lactato Desidrogenase/imunologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/virologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Interleukin 9 (IL-9) is a cytokine linked to lung inflammation, but its cellular origin and function remain unclear. Here we describe a reporter mouse strain designed to map the fate of cells that have activated IL-9. We found that during papain-induced lung inflammation, IL-9 production was largely restricted to innate lymphoid cells (ILCs). IL-9 production by ILCs depended on IL-2 from adaptive immune cells and was rapidly lost in favor of other cytokines, such as IL-13 and IL-5. Blockade of IL-9 production via neutralizing antibodies resulted in much lower expression of IL-13 and IL-5, which suggested that ILCs provide the missing link between the well-established functions of IL-9 in the regulation of type 2 helper T cell cytokines and responses.
Assuntos
Citocinas/metabolismo , Interleucina-9/metabolismo , Linfócitos/metabolismo , Pneumonia/imunologia , Células Th2/imunologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Células Cultivadas , Citocinas/imunologia , Genes Reporter/genética , Imunidade Inata , Interleucina-9/genética , Interleucina-9/imunologia , Pulmão , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papaína/administração & dosagem , Comunicação Parácrina , Pneumonia/induzido quimicamente , Células Th2/efeitos dos fármacosRESUMO
For effective treatments and preventive measures against severe COVID-19, it is essential to determine early markers of disease severity in different populations. We analysed the cytokine kinetics of 129 COVID-19 patients with mild symptoms, 68 severe cases, and 20 healthy controls for the first time in Rwanda. Pro-inflammatory (IFNγ, IL-6, TNFα), Treg (IL-10, TGFß1, TGFß3), Th9 (IL-9), Th17 (IL-17), and Th2 (IL-4, IL-13) cytokines, total IgM and IgG, as well as gene expressions of FoxP3, STAT5+, IFNγ-R1, and ROR alpha+, were measured at day 1, day 7, day 14, day 21, and day 28 post-infection. Severe cases showed a significantly stronger increase than mild patients in levels of all cytokines (except IL-9) and all gene expression on day 1 of infection. Some cytokine levels dropped to levels comparable to mild cases at later time points. Further analysis identified IFNγ as a marker of severity throughout the disease course, while TGFß1, IL-6, and IL-17 were markers of severity only at an early phase. Importantly, this study revealed a striking low IL-9 level and high IFNγ/IL-9 ratio in the plasma of patients who later died compared to mild and severe cases who recovered, suggesting that this could be an important biomarker for predicting the severity of COVID-19 and post-COVID-19 syndrome.
Assuntos
COVID-19 , Citocinas , Humanos , Citocinas/genética , Interleucina-17/genética , Interleucina-9/genética , Interleucina-6 , Cinética , Síndrome de COVID-19 Pós-Aguda , Ruanda/epidemiologia , Interferon gama , Gravidade do PacienteRESUMO
The dimeric cytokine IL-12 is important in the control of various infections but also contributes to the pathology of certain diseases making it a potential target for therapy. However, its specific inhibition with antibodies is complicated by the fact that its two subunits are present in other cytokines: p40 in IL-23 and p35 in IL-35. This has led to erroneous conclusions like the alleged implication of IL-12 in experimental autoimmune encephalomyelitis (EAE). Here, we report the development of a mouse anti-mouse IL-12 vaccine and the production of monoclonal antibodies (mAbs) that do not react with p40 or p35 (in IL-35) but specifically recognize and functionally inhibit the IL-12 heterodimer. Using one of these mAbs, MM12A1.6, that strongly inhibited IFN-γ production and LPS-induced septic shock after viral infection, we demonstrate the critical role played by IL-12 in the rejection of male skin graft by female C57BL/6 syngeneic recipients and in the clearance of an immunogenic mastocytoma tumor variant by DBA/2 mice, but not in a parent to F1 immune aggression model nor in MOG-induced EAE, which was clearly prevented by anti-p40 mAb C17.8. Given this selective inhibition of IL-12, these mAbs provide new options for reassessing IL-12 function in vivo.
Assuntos
Anticorpos Monoclonais/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Rejeição de Enxerto/imunologia , Interleucina-12/metabolismo , Mastocitoma/imunologia , Esclerose Múltipla/imunologia , Infecções por Nidovirales/imunologia , Nidovirales/fisiologia , Subunidades Proteicas/metabolismo , Sepse/imunologia , Transplante de Pele , Animais , Anticorpos Monoclonais/isolamento & purificação , Modelos Animais de Doenças , Epitopos , Humanos , Hibridomas , Interleucina-12/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Neoplasias Experimentais , Subunidades Proteicas/imunologiaRESUMO
The proper control of Plasmodium infection requires a finely balanced immune response. Here, we evaluated the implication of TGF-ß1 and TGF-ß3 in this process using novel monoclonal antibodies to measure their plasma concentrations in comparison with other cytokines and the expression of FOXP3 mRNA. Plasma cytokine levels were measured in 80 patients with severe anaemic malaria and 186 with a mild presentation using ELISA, and rtPCR was used to measure FOXP3 mRNA expression. While no mature TGF-ß isoforms were detected in the plasma, the latent TGF-ß1 and TGF-ß3 were strongly upregulated in patients with mild malaria and nearly undetected in patients with severe disease. Similar selective upregulation in mild patients was observed for IL-9 and FOXP3 mRNA, while IL-7, IL-10, IL-17, and IL-27, although higher in mild cases, were also detected in severe disease. In contrast, a clearly skewed trend of severe cases towards higher pro-inflammatory (IL-6, IL-13, TNF-α) and Th1 (IFN-γ) responses was observed, which was associated with a higher level of parasitaemia as well as lower IgG and higher IgM responses. Together, these results suggest that the stimulation of regulatory T cells through TGF-ß1/TGF-ß3 and IL-9 is paramount to an effective and balanced protective immunity in natural human malaria infection.
Assuntos
Interleucina-27 , Malária , Humanos , Interleucina-10 , Fator de Crescimento Transformador beta1/genética , Interleucina-13 , Interleucina-17 , Interleucina-9/genética , Fator de Necrose Tumoral alfa , Regulação para Cima , Fator de Crescimento Transformador beta3 , Interleucina-6 , Interleucina-7 , Citocinas , Fator de Crescimento Transformador beta , RNA Mensageiro , Imunoglobulina M , Imunoglobulina G , Fatores de Transcrição Forkhead , Anticorpos MonoclonaisRESUMO
Since the discovery of T helper type 1 and type 2 effector T cell subsets 20 years ago, inducible regulatory T cells and interleukin 17 (IL-17)-producing T helper cells have been added to the 'portfolio' of helper T cells. It is unclear how many more effector T cell subsets there may be and to what degree their characteristics are fixed or flexible. Here we show that transforming growth factor-beta, a cytokine at the center of the differentiation of IL-17-producing T helper cells and inducible regulatory T cells, 'reprograms' T helper type 2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drives the differentiation of 'T(H)-9' cells directly. Thus, transforming growth factor-beta constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways.
Assuntos
Diferenciação Celular/imunologia , Interleucina-9/biossíntese , Subpopulações de Linfócitos T/citologia , Células Th2/citologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem da Célula/imunologia , Citocinas/biossíntese , Camundongos , Camundongos Transgênicos , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologia , Células Th2/imunologiaRESUMO
The pathogenic role of IL-17 and GM-CSF has been unravelled in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). However, in most models, EAE is characterised by a monophasic attack which is not representative of the relapsing nature nor the chronicity displayed in MS. Here, we used proteolipid protein peptide (PLP139-151 ) to trigger EAE-relapses (EAE-II) in SJL mice that had recovered from a primary-EAE episode (EAE-I). This procedure resulted in severe and irreversible disease that, unlike EAE-I, was not abolished by anti-IL-17-mAb. In contrast, prophylactic anti-GM-CSF-mAb treatment prevented EAE-I and -II. Strikingly, the expression of T-cell transcription factors and cytokines/chemokines in mice treated with anti-GM-CSF during both EAE episodes was silenced. Anti-GM-CSF-mAb treatment administered only during EAE-II did not completely prevent relapses but mice ultimately reached full recovery. Anti-GM-CSF treatment also strongly impaired and ultimately resolved monophasic MOG35-55 -induced EAE in C57Bl/6 mice. In such protected mice, anti-GM-CSF treatment also prevented a further relapse induced by MOG-revaccination. These results underscore the critical role of GM-CSF on pro-inflammatory mediator production. Furthermore, we observed a strong preventive and curative effect of anti-GM-CSF neutralisation in two EAE models, relapsing and chronic. Altogether these findings are relevant for further MS research.
Assuntos
Anticorpos Monoclonais/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-17/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/metabolismo , Recidiva , Fatores de Transcrição/metabolismoRESUMO
In spite of considerable therapeutic progress, acute graft-versus-host disease still limits allogeneic hematopoietic cell transplantation. We recently reported that mouse infection with nidovirus lactate dehydrogenase elevating virus impairs disease in non-conditioned B6D2F1 recipients of parental B6 spleen cells. As this virus activates TLR7, we tested a pharmacological TLR7 ligand, R848, in this model and observed complete survival if donor and recipients were treated before transplantation. Mixed lymphocyte culture performed 48 h after R848-treatment of normal mice demonstrated that both T-cell allo-responsiveness and antigen presentation by CD11b+ and CD8α+ dendritic cells were inhibited. These inhibitions were dependent on IFNAR-1 signaling. In the B6 to B6D2F1 transplantation model, R848 decelerated, but did not abrogate, donor T-cell implantation and activation. However, it decreased interferon-gamma, tumor necrosis factor-alpha and interleukin-27 while upregulating active transforming growth factor-beta 1 plasma levels. In addition, donor and recipient Foxp3+ regulatory T-cell numbers were increased in recipient mice and their elimination compromised disease prevention. R848 also strongly improved survival of lethally irradiated BALB/c recipients of B6 hematopoietic cells and this also correlated with an upregulation of CD4 and CD8 Foxp3+ regulatory T cells that could be further increased by inhibition of interleukin-27. The combination of anti-interleukin-27p28 mono -clonal antibody and R848 showed strong synergy in preventing disease in the B6 to B6D2F1 transplantation model when recipients were sublethally irradiated and this also correlated with upregulation of regulatory T cells. We conclude that R848 modulates multiple aspects of graft-versus-host disease and offers potential for safe allogeneic bone marrow transplantation that can be further optimized by inhibition of interleukin-27.
Assuntos
Anticorpos Monoclonais/farmacologia , Doença Enxerto-Hospedeiro/prevenção & controle , Imidazóis/farmacologia , Interleucina-27/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Receptor 7 Toll-Like/metabolismo , Animais , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Imunomodulação/efeitos dos fármacos , Ligantes , Melanoma Experimental , Camundongos , Transplante de Neoplasias , Linfócitos T Reguladores/imunologiaRESUMO
Reestablishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft-versus-host disease (GVHD), and recalibrate the effector and regulatory arms of the immune system. However, clinically feasible, cost-effective strategies that do not require extensive ex vivo cellular manipulation have remained elusive. In the current study, we demonstrate that inhibition of the interleukin-27p28 (IL-27p28) signaling pathway through antibody blockade or genetic ablation prevented lethal GVHD in multiple murine transplant models. Moreover, protection from GVHD was attributable to augmented global reconstitution of CD4+ natural regulatory T cells (nTregs), CD4+ induced Tregs (iTregs), and CD8+ iTregs, and was more potent than temporally concordant blockade of IL-6 signaling. Inhibition of IL-27p28 also enhanced the suppressive capacity of adoptively transferred CD4+ nTregs by increasing the stability of Foxp3 expression. Notably, blockade of IL-27p28 signaling reduced T-cell-derived-IL-10 production in conventional T cells; however, there was no corresponding effect in CD4+ or CD8+ Tregs, indicating that IL-27 inhibition had differential effects on IL-10 production and preserved a mechanistic pathway by which Tregs are known to suppress GVHD. Targeting of IL-27 therefore represents a novel strategy for the in vivo expansion of Tregs and subsequent prevention of GVHD without the requirement for ex vivo cellular manipulation, and provides additional support for the critical proinflammatory role that members of the IL-6 and IL-12 cytokine families play in GVHD biology.
Assuntos
Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Interleucinas/antagonistas & inibidores , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Transdução de Sinais/genética , Linfócitos T Reguladores/patologiaRESUMO
T helper (Th)17 immune response participates in allergic lung inflammation and asthma is reduced in the absence of interleukin (IL)-17 in mice. Since IL-17A and IL-17F are induced and bind the shared receptor IL-17RA, we asked whether both IL-17A and IL-17F contribute to house dust mite (HDM) induced asthma. We report that allergic lung inflammation is attenuated in absence of either IL-17A or IL-17F with reduced airway hyperreactivity, eosinophilic inflammation, goblet cell hyperplasia, cytokine and chemokine production as found in absence of IL-17RA. Furthermore, specific antibody neutralization of either IL-17A or IL-17F given during the sensitization phase attenuated allergic lung inflammation and airway hyperreactivity. In vitro activation by HDM of primary dendritic cells revealed a comparable induction of CXCL1 and IL-6 expression and the response to IL-17A and IL-17F relied on IL-17RA signaling via the adaptor protein act1 in fibroblasts. Therefore, HDM-induced allergic respiratory response depends on IL-17RA via act1 signaling and inactivation of either IL-17A or IL-17F is sufficient to attenuate allergic asthma in mice.
Assuntos
Asma/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Pyroglyphidae/imunologia , Alérgenos/imunologia , Animais , Asma/imunologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Interleucina-17/imunologia , Interleucina-6/imunologia , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Células Th17/imunologia , Células Th2/imunologiaRESUMO
Female mice of inbred strain CBA do not reject syngeneic male skin grafts even though they mount a T-cell response against the male-specific HY antigen. We show that local immunostimulation performed by injecting cytokines and Toll-like receptor ligands in close vicinity to the graft causes rejection. We feel that this approach should be tested in tumor-bearing human patients in combination with antitumor vaccination. Relief of intratumor immunosuppression may increase considerably the fraction of patients who respond to vaccination directed against tumor antigens recognized by T cells.
Assuntos
Modelos Animais de Doenças , Rejeição de Enxerto/induzido quimicamente , Tolerância Imunológica/imunologia , Imunização/métodos , Neoplasias/terapia , Transferência Adotiva , Animais , Citocinas/efeitos adversos , Citocinas/imunologia , Primers do DNA/genética , Feminino , Imunização/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Neoplasias/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores Sexuais , Transplante de Pele/métodosRESUMO
Periostin (POSTN), a secreted homodimeric protein that binds integrins αvß3, αvß5, and α6ß4, was originally found to be expressed in fetal tissues and in the adult upon injury particularly bone fractures due to its role in remodelling and repair. Recently it was found to be over-expressed in human breast cancer and a variety of other tumour types including head and neck squamous cell carcinoma, where its overexpression correlates with increased tumour invasion. Progress in studying its functional role in tumour pathogenesis has been hampered by the paucity of antibodies for its specific and sensitive detection. It has proven very difficult to obtain monoclonal antibodies (mAbs) against this highly conserved protein but we report here that combining infection of mice with lactate dehydrogenase elevating virus (LDV), a B cell activating arterivirus, with conjugation of human POSTN to ovalbumin as an immunogenic carrier, enabled us to develop six mAbs recognizing both human and mouse POSTN and inhibiting its binding to αvß3 integrin. Two of the mAbs, MPB4B1 and MPC5B4, were tested and found to inhibit POSTN-induced migration of human endothelial colony forming cells. All six mAbs recognized amino acids 136-51 (APSNEAWDNLDSDIRR) within the POSTN fascilin (FAS) 1-1 domain revealing the functional importance of this motif; this was further highlighted by the ability of aa 136-151 peptide to inhibit integrin-mediated cell migration. Immunohistochemistry using MPC5B4, indicated that breast tumour cell POSTN expression was a strong prognostic indicator, along with tumour size, lymph node, and human epidermal growth factor receptor 2 (HER2) status.
Assuntos
Anticorpos Monoclonais , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Moléculas de Adesão Celular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Motivos de Aminoácidos , Animais , Especificidade de Anticorpos , Sítios de Ligação de Anticorpos , Neoplasias da Mama/metabolismo , Movimento Celular/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Pessoa de Meia-Idade , Análise Serial de TecidosRESUMO
Acute graft versus host disease (aGVHD) remains a life-threatening complication of bone marrow transplantation. Here we show that IL-27, a member of the IL-12 cytokine family, plays an essential role in a parent-to-F1 murine aGVHD model, using B6 mice as parents and B6D2 mice as F1 recipients. IL-27 is transiently detectable in the serum of B6D2 recipients of B6 spleen cells, with a peak at day 10. Treatment with anti-IL-27p28 mAb MM27.7B1 (αp28Ab), at the time of and six days after B6 cell transfer, blocked GVHD. Protection was associated with host cell survival and undiminished engraftment of donor cells, lack of host B-cell depletion, increased Th2-type immunoglobulin production, a decrease in serum IFN-γ, a drop in anti-H-2D(d) cytotoxic T lymphocyte activity and an increase in Foxp3(+) T cells. We therefore conclude that IL-27 plays a critical role in the parent-to-F1 model of aGVHD and that blocking IL-27 could have therapeutic relevance.
Assuntos
Doença Enxerto-Hospedeiro/etiologia , Interleucinas/fisiologia , Doença Aguda , Animais , Proliferação de Células , Feminino , Interferon gama/fisiologia , Interleucinas/antagonistas & inibidores , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Redução de PesoRESUMO
Despite their relevance to mucosal defense, production of IgA and the function of lung B-cells remain unknown in chronic obstructive pulmonary disease (COPD). We assessed IgA synthesis in the lungs of COPD (n=28) and control (n=21) patients, and regulation of B-cells co-cultured with in vitro-reconstituted airway epithelium. In COPD lung tissue, synthesis of IgA1 was increased, which led to its accumulation in subepithelial areas. In vitro, the COPD bronchial epithelium imprinted normal human B-cells for increased production of IgA (mainly IgA1) and maturation into CD38(+) plasma cells. These effects were associated with upregulation of TACI (transmembrane activator and CAML interactor) and were observed under resting conditions, while being partly inhibited upon stimulation with cigarette smoke extract. Interleukin (IL)-6 and BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) were upregulated in the COPD epithelium and lung tissue, respectively; the IgA-promoting effect of the COPD bronchial epithelium was inhibited by targeting IL-6 and, to a lower extent, by blocking TACI. These data show that in COPD, the bronchial epithelium imprints B-cells with signals promoting maturation into IgA-producing plasma cells through the action of two epithelial/B-cell axes, namely the IL-6/IL-6 receptor and BAFF-APRIL/TACI pathways, while cigarette smoke partly counteracts this IgA-promoting effect.
Assuntos
Imunoglobulina A/metabolismo , Interleucina-6/metabolismo , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Biomarcadores , Estudos de Casos e Controles , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Reação em Cadeia da Polimerase/métodos , RNA/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Sensibilidade e Especificidade , Transdução de Sinais , Estatísticas não ParamétricasRESUMO
Th17 cells are a proinflammatory subset of effector T cells that have been implicated in the pathogenesis of asthma. Their production of the cytokine IL-17 is known to induce local recruitment of neutrophils, but the direct impact of IL-17 on the lung epithelium is poorly understood. In this study, we describe a novel mouse model of spontaneous IL-17-driven lung inflammation that exhibits many similarities to asthma in humans. We have found that STAT3 hyperactivity in T lymphocytes causes an expansion of Th17 cells, which home preferentially to the lungs. IL-17 secretion then leads to neutrophil infiltration and lung epithelial changes, in turn leading to a chronic inflammatory state with increased mucus production and decreased lung function. We used this model to investigate the effects of IL-17 activity on airway epithelium and identified CXCL5 and MIP-2 as important factors in neutrophil recruitment. The neutralization of IL-17 greatly reduces pulmonary neutrophilia, underscoring a key role for IL-17 in promoting chronic airway inflammation. These findings emphasize the role of IL-17 in mediating neutrophil-driven pulmonary inflammation and highlight a new mouse model that may be used for the development of novel therapies targeting Th17 cells in asthma and other chronic pulmonary diseases.
Assuntos
Asma/imunologia , Doenças do Sistema Imunitário/imunologia , Interleucina-17/imunologia , Transtornos Leucocíticos/imunologia , Neutrófilos/imunologia , Mucosa Respiratória/imunologia , Animais , Asma/metabolismo , Separação Celular , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Pneumonia/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , TransfecçãoRESUMO
Although many cells undergo transformation, few actually develop into tumours, due to successful mechanisms of immunosurveillance. To investigate whether an infectious agent may play a role in this process, the growth of a plasmacytoma was investigated in mice infected by lactate dehydrogenase-elevating virus. Acutely infected animals were significantly protected against tumour development. The mechanisms responsible for this protection were analysed in mice deficient for relevant immune cells or molecules and after in vivo cell depletion. This protection by viral infection correlated with NK cell activation and with IFN-γ production. It might also be related to activation of NK/T-cells, although this remains to be proven formally. Therefore, our results indicated that infections with benign micro-organisms may protect the host against cancer development, through non-specific stimulation of the host's innate immune system and especially of NK cells.
Assuntos
Células Matadoras Naturais/imunologia , Vírus Elevador do Lactato Desidrogenase/imunologia , Vírus Oncolíticos/imunologia , Plasmocitoma/imunologia , Plasmocitoma/prevenção & controle , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos KnockoutRESUMO
BACKGROUND: Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiologic and immunologic processes are not fully understood. OBJECTIVE: The aim of this study was to determine whether TH9 cells develop in vivo in a model of chronic airway hyperreactivity (AHR) and what factors control this development. METHOD: We have developed a novel chronic allergen exposure model using the clinically relevant antigen Aspergillus fumigatus to determine the time kinetics of TH9 development in vivo. RESULTS: TH9 cells were detectable in the lungs after chronic allergen exposure. The number of TH9 cells directly correlated with the severity of AHR, and anti-IL-9 treatment decreased airway inflammation. Moreover, we have identified programmed cell death ligand (PD-L) 2 as a negative regulator of TH9 cell differentiation. Lack of PD-L2 was associated with significantly increased TGF-ß and IL-1α levels in the lungs, enhanced pulmonary TH9 differentiation, and higher morbidity in the sensitized mice. CONCLUSION: Our findings suggest that PD-L2 plays a pivotal role in the regulation of TH9 cell development in chronic AHR, providing novel strategies for modulating adaptive immunity during chronic allergic responses.
Assuntos
Hiper-Reatividade Brônquica/genética , Interleucina-9/imunologia , Pulmão/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/genética , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa , Alérgenos/imunologia , Animais , Anticorpos/imunologia , Aspergillus fumigatus/imunologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Diferenciação Celular/imunologia , Doença Crônica , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Interleucina-1alfa/imunologia , Pulmão/metabolismo , Pulmão/patologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/patologia , Fator de Crescimento Transformador beta/imunologiaRESUMO
A commonly used mouse model of asthma is based on i.p. sensitization to OVA together with aluminum hydroxide (alum). In wild-type BALB/c mice, subsequent aerosol challenge using this protein generates an eosinophilic inflammation associated with Th2 cytokine expression. By constrast, in DO11.10 mice, which are transgenic for an OVA-specific TCR, the same treatment fails to induce eosinophilia, but instead promotes lung neutrophilia. In this study, we show that this neutrophilic infiltration results from increased IL-17A and IL-17F production, whereas the eosinophilic response could be restored upon blockade of IFN-γ, independently of the Th17 response. In addition, we identified a CD4(+) cell population specifically present in DO11.10 mice that mediates the same inflammatory response upon transfer into RAG2(-/-) mice. This population contained a significant proportion of cells expressing an additional endogenous TCR α-chain and was not present in RAG2(-/-) DO11.10 mice, suggesting dual antigenic specificities. This particular cell population expressed markers of memory cells, secreted high levels of IL-17A, and other cytokines after short-term restimulation in vitro, and triggered a neutrophilic response in vivo upon OVA aerosol challenge. The relative numbers of these dual TCR lymphocytes increased with the age of the animals, and IL-17 production was abolished if mice were treated with large-spectrum antibiotics, suggesting that their differentiation depends on foreign Ags provided by gut microflora. Taken together, our data indicate that dual TCR expression biases the OVA-specific response in DO11.10 mice by inhibiting eosinophilic responses via IFN-γ and promoting a neutrophilic inflammation via microbiota-induced Th17 differentiation.
Assuntos
Diferenciação Celular/imunologia , Quimiotaxia de Leucócito/imunologia , Neutrófilos/imunologia , Pneumonia/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Separação Celular , Citometria de Fluxo , Interferon gama/biossíntese , Interleucina-17/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Ovalbumina/imunologia , Pneumonia/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Th17/metabolismo , Células Th17/microbiologiaRESUMO
Auto-vaccination is a procedure that recently attracted the interest of a growing number of investigators as an alternative to gene inactivation for functional studies of cytokines or other mediators. It is based on the observation that autologous cytokines cross-linked to a foreign protein or peptide are recognized by self-reactive B cells that present foreign peptides, and by doing so attract illicit help from helper T cells that recognize the foreign peptide on the self-reactive B cell MHC Class II complex. This leads to the production of antibodies reacting with self-proteins and thus to neutralization of the targeted factor. Here, we summarize the different techniques that were successful in breaking this self-tolerance and provide several examples of the functional consequences of these auto-vaccines. An additional output of auto-vaccination is the production of mouse monoclonal antibodies against mouse factors. Such antibodies have obvious advantages for long-term use in vivo.