RESUMO
CD4+ FOXP3+ Tregs are currently explored to develop cell therapies against immune-mediated disorders, with an increasing focus on antigen receptor-engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG-3 and CTLA-4 in LNs, while IL-10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL-10, CTLA-4, and LAG-3 were nonredundantly required for the protective function of antigen receptor-engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg-derived IL-10 and CTLA-4 were both required to suppress acute autoreactive CD4+ T-cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor-engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks.
Assuntos
Autoimunidade , Doenças do Sistema Imunitário , Animais , Antígeno CTLA-4 , Terapia Baseada em Transplante de Células e Tecidos , Fatores de Transcrição Forkhead/genética , Interleucina-10 , Camundongos , Receptores de Antígenos , Linfócitos T ReguladoresRESUMO
Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis.
Assuntos
Bacteriemia/microbiologia , Modelos Animais de Doenças , Proteínas de Fímbrias/metabolismo , Fímbrias Bacterianas/fisiologia , Infecções Meningocócicas/microbiologia , Neisseria meningitidis/patogenicidade , Sepse/microbiologia , Animais , Bacteriemia/metabolismo , Bacteriemia/patologia , Aderência Bacteriana , Células Endoteliais , Feminino , Proteínas de Fímbrias/genética , Humanos , Infecções Meningocócicas/metabolismo , Infecções Meningocócicas/patologia , Camundongos , Camundongos SCID , Sepse/metabolismo , Sepse/patologia , Transplante de PeleRESUMO
Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) require exposure to IL-23 to become encephalitogenic, but the mechanism by which IL-23 promotes their pathogenicity is not known. Here we found that IL-23 induced production of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in T(H)17 cells and that GM-CSF had an essential role in their encephalitogenicity. Our findings identify a chief mechanism that underlies the important role of IL-23 in autoimmune diseases. IL-23 induced a positive feedback loop whereby GM-CSF secreted by T(H)17 cells stimulated the production of IL-23 by antigen-presenting cells. Such cross-regulation of IL-23 and GM-CSF explains the similar pattern of resistance to autoimmunity when either of the two cytokines is absent and identifies T(H)17 cells as a crucial source of GM-CSF in autoimmune inflammation.
Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-1/farmacologia , Interleucina-23/farmacologia , Células Th17/efeitos dos fármacos , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Antígeno CD11c/imunologia , Antígeno CD11c/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Técnicas de Cocultura , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Feminino , Citometria de Fluxo , Glicoproteínas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interleucina-1beta/farmacologia , Interleucina-23/imunologia , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fragmentos de Peptídeos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Excessive inflammation occurs during infection and autoimmunity in mice lacking the alpha-subunit of the interleukin 27 (IL-27) receptor. The molecular mechanisms underlying this increased inflammation are incompletely understood. Here we report that IL-27 upregulated IL-10 in effector T cells that produced interferon-gamma and expressed the transcription factor T-bet but did not express the transcription factor Foxp3. These IFN-gamma+T-bet+Foxp3- cells resembled effector T cells that have been identified as the main source of host-protective IL-10 during inflammation. IL-27-induced production of IL-10 was associated with less secretion of IL-17, and exogenous IL-27 reduced the severity of adoptively transferred experimental autoimmune encephalomyelitis by a mechanism dependent on IL-10. Our data show that IL-27-induced production of IL-10 by effector T cells contributes to the immunomodulatory function of IL-27.
Assuntos
Autoimunidade/efeitos dos fármacos , Encefalomielite Autoimune Experimental/imunologia , Interleucina-10/metabolismo , Interleucina-17/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T/metabolismo , Animais , Autoimunidade/imunologia , Doenças do Sistema Nervoso Central/imunologia , Doenças do Sistema Nervoso Central/patologia , Inflamação/imunologia , Interleucina-10/imunologia , Interleucina-17/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Linfócitos T/imunologiaRESUMO
One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells. Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies.
Assuntos
Imunidade Adaptativa/fisiologia , Doenças Desmielinizantes/imunologia , Bainha de Mielina/imunologia , Adolescente , Adulto , Idoso , Animais , Transplante de Células , Quimiocina CCL19/imunologia , Feminino , Humanos , Linfócitos/imunologia , Lisofosfatidilcolinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Células-Tronco Neurais/imunologia , Oligodendroglia/imunologia , Oligodendroglia/patologia , Adulto JovemRESUMO
IL-17-secreting CD8(+) T cells (Tc17 cells) have been implicated in immunity to infections, cancer, and autoimmune diseases. Thus far, studies on Tc17 cells have primarily investigated their development from naïve precursors, while the biology of committed Tc17 cells has been less characterized, in particular during the effector phase of immune responses. IL-27 is an important regulator of inflammation through the induction of regulatory Tr1 cells, as well as a suppressor of Th17-cell development. IL-27 suppresses the development of Tc17 cells, but its effects on committed Tc17 cells are unknown. Here we demonstrate that even though IL-27 completely inhibited the development of C57BL/6 mouse Tc17 cells, it had little effect on previously committed Tc17 cells. Although committed Tc17 cells were capable of responding to IL-27, it had no effect on expression of RORγt and RORα, or production of various cytokines. Committed Tc17 cells did not express granzyme B and lacked cytotoxicity in vitro, features that remained unaltered by IL-27 treatment. Nonetheless, they efficiently induced diabetes, irrespective of treatment with IL-27 prior to transfer into RIP-mOVA mice. These findings suggest that use of IL-27 to modulate autoimmune diseases might have limited therapeutic efficacy if autoaggressive Tc17 cells have already developed.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucina-27/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Citometria de Fluxo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-27/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacosRESUMO
The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D+CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+CD27- and memory IgD-CD27+ B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans.
Assuntos
Linfócitos B , Proteínas Proto-Oncogênicas c-akt , Humanos , Camundongos , Animais , Tecido Linfoide , Transdução de Sinais , BaçoRESUMO
IL-27 counters the effect of TGF-beta+IL-6 on naive CD4(+) T cells, resulting in near complete inhibition of de novo Th17 development. In contrast, little is known about the effect of IL-27 on already differentiated Th17 cells. A better understanding of how IL-27 regulates these cells is needed to evaluate the therapeutic potential of IL-27 in Th17 cells-associated diseases. In this study, we show that IL-27 had surprisingly little effect on committed Th17 cells, despite its expression of a functional IL-27R. Contrary to de novo differentiation of Th17 cells, IL-27 did not suppress expression of retinoid-related orphan receptor (ROR)gammat or RORalpha in committed Th17 cells. Consistent with this finding, the frequency of committed Th17 cells and their cytokine secretion remained unaffected by IL-27. Both memory Th17 cells (CD4(+)CD25(-)CD62L(low)) that developed in vivo and encephalitogenic Th17 cells infiltrating the CNS of mice developing experimental autoimmune encephalomyelitis produced similar amounts of IL-17A when reactivated with IL-23 in the absence and presence of exogenous IL-27. Finally, IL-27 failed to suppress encephalitogenicity of Th17 cells in an adoptive transfer of experimental autoimmune encephalomyelitis. Analysis ex vivo of transferred Th17 cells in the spleen and CNS of recipient mice showed that cells retained similar phenotype irrespective of whether cells were treated or not with IL-27. Our data demonstrate that in contrast to inhibition of de novo differentiation of Th17 cells, IL-27 has little or no effect on committed Th17 cells. These findings indicate that therapeutic applications of IL-27 might have a limited efficacy in inflammatory conditions where aggressive Th17 responses have already developed.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/imunologia , Interleucinas/farmacologia , Receptores do Ácido Retinoico/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Transferência Adotiva , Animais , Citocinas/biossíntese , Citocinas/imunologia , Feminino , Glicoproteínas/imunologia , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/imunologia , Receptores de Citocinas/imunologia , Receptores de Citocinas/metabolismo , Receptores do Ácido Retinoico/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
IL-17-producing CD8(+) T cells (Tc17) appear to play a role in a range of conditions, such as autoimmunity and cancer. Thus far, Tc17 cells have been only marginally studied, resulting in a paucity of data on their biology and function. We demonstrate that Tc17 and Th17 cells share similar developmental characteristics, including the previously unknown promoting effect of IL-21 on Tc17 cell differentiation and IL-23-dependent expression of IL-22. Both STAT1 and STAT4 are required for optimal development of Tc17 cells and maximal secretion of cytokines. Tc17 cells are cytotoxic, and they can be either pathogenic or nonpathogenic upon adoptive transfer in the model of autoimmune diabetes. Tc17 cells treated with TGF-beta1 plus IL-6 are not diabetogenic, whereas IL-23-treated cells potently induce the disease. IL-17A and IL-17F are necessary but not sufficient for diabetes induction by Tc17 cells. Tc17 cells treated with TGF-beta1 plus IL-6 or IL-23 likely differ in pathogenicity due to their disparate capacity to attract other immune cells and initiate inflammation.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Interleucina-17/biossíntese , Interleucina-23/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Células Cultivadas , Testes Imunológicos de Citotoxicidade , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Imunofenotipagem , Interleucina-17/metabolismo , Interleucina-17/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos TransgênicosRESUMO
We reduced EAE severity by using two anti-allergic drugs. A control group of mice received i.p. injections of PBS as vehicle while a further two groups were treated either with pyrilamine, a histamine receptor 1 antagonist or with CV6209, a platelet activating factor receptor antagonist. Our results showed that the blockade of the responses to both histamine and PAF leads together to a decline in clinical signs of EAE and significant changes in the serum IgG recognition of some healthy brain antigenic targets. We characterized two discriminant antigens: internexin neuronal intermediate filament protein, and malate dehydrogenase 1, which were able to clearly distinguish untreated mice from treated mice. Their role as potent targets in pathogenic and/or neuroprotective processes is discussed.
Assuntos
Antialérgicos/farmacologia , Anticorpos Anti-Idiotípicos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Imunoglobulina G/imunologia , Animais , Anticorpos Anti-Idiotípicos/sangue , Sistema Nervoso Central/imunologia , Eletroforese , Feminino , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Immunoblotting , Proteínas de Filamentos Intermediários/imunologia , Malato Desidrogenase/imunologia , Camundongos , Camundongos Endogâmicos , Fator de Ativação de Plaquetas/antagonistas & inibidores , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Proteômica , Compostos de Piridínio/farmacologia , Pirilamina/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Numerous studies have demonstrated the role of immune cells, in particular macrophages, in central nervous system (CNS) pathologies. There are two main macrophage populations in the CNS: (i) the microglia, which are the resident macrophages of the CNS and are derived from yolk sac progenitors during embryogenesis, and (ii) the monocyte-derived macrophages (MDM), which can infiltrate the CNS during disease and are derived from bone marrow progenitors. The roles of each macrophage subpopulation differ depending on the pathology being studied. Furthermore, there is no consensus on the histological markers or the distinguishing criteria used for these macrophage subpopulations. However, the analysis of the expression profiles of the CD11b and CD45 markers by flow cytometry allows us to distinguish the microglia (CD11b+CD45med) from the MDM (CD11b+CD45high). In this protocol, we show that the density gradient centrifugation and the flow cytometry analysis can be used to characterize these CNS macrophage subpopulations, and to study several markers of interest expressed by these cells as we recently published. Thus, this technique can further our understanding of the role of macrophages in mouse models of neurological diseases and can also be used to evaluate drug effects on these cells.
Assuntos
Sistema Nervoso Central/citologia , Citometria de Fluxo/métodos , Macrófagos/imunologia , Microglia/imunologia , Animais , Biomarcadores/análise , Antígeno CD11b/biossíntese , Sistema Nervoso Central/imunologia , Antígenos Comuns de Leucócito/biossíntese , Macrófagos/citologia , Camundongos , Microglia/citologiaRESUMO
We sequentially analyzed the serum IgG response against normal mouse brain during experimental autoimmune encephalomyelitis in SJL/J mice injected with CFA, Bordetella pertussis toxin (BPT) and proteolipid protein 139-151 peptide, compared with mice that received CFA and BPT or were uninjected. Dynamic changes were observed from day 0 to day 28 in the 3 groups. Six highly discriminant antigenic bands (kappa=0.974) were identified. Three non-myelin proteins were characterized (mitochondrial aconitase hydratase 2, phosphoglycerate mutase 1, brain specific pyruvate deshydrogenase). The IgG response against two of them was less frequent in EAE whereas it was associated with multiple sclerosis in our previous work.
Assuntos
Autoantígenos/imunologia , Encéfalo/imunologia , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/imunologia , Imunoglobulina G/sangue , Aconitato Hidratase/imunologia , Animais , Autoanticorpos/sangue , Western Blotting , Feminino , Camundongos , Proteína Proteolipídica de Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Fosfoglicerato Mutase/imunologia , Complexo Piruvato Desidrogenase/imunologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
We described previously a CTL clone able to lyse the autologous carcinoma cell line IGR-Heu after specific recognition of an HLA-A2/mutated alpha-actinin-4 peptide complex. Here, we used IGR-Heu, cultured either as standard two-dimensional monolayers or as three-dimensional spheroids, to further analyze the influence of target architecture on CTL reactivity. Interestingly, we found that changes in the tumor structure from two- to three-dimensional induced a dramatic decrease in its capacity to activate autologous CTL, as measured by IFN-gamma and tumor necrosis factor-alpha secretion. These functional alterations were attributable neither to MHC class I expression nor to tumor antigen (Ag) down-regulation, because IGR-Heu, cultured as two- or three-dimensional, expressed similar levels of HLA-A2 and alpha-actinin-4. More importantly, incubation of three-dimensional cells with synthetic epitope completely restored cytokine release by CTL. This defective Ag presentation correlated with a decrease in heat shock protein (hsp)70 expression by three-dimensional tumors compared with two-dimensional cells. Furthermore, transfection of the tumor cells with hsp70 cDNA completely restored the Ag-presenting potential of spheroids and, therefore, cytokine production by T cells. These data strongly suggest that hsp70 down-regulation in three-dimensional cells may result in tumor resistance to the immune response.
Assuntos
Apresentação de Antígeno/imunologia , Carcinoma de Células Grandes/imunologia , Proteínas de Choque Térmico HSP70/genética , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral , Linfócitos T Citotóxicos/imunologia , Sequência de Bases , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologia , Primers do DNA , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Animal models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) are inflammatory demyelinating diseases which comprise a heterogeneous group of disorders that affect the peripheral and central nervous systems. EAE presents close similarities with multiple sclerosis (MS), a chronic inflammatory disease affecting central nervous system (CNS) white matter. Many studies have shown EAE to be a particularly useful animal model for the understanding of both the mechanisms of immune-mediated CNS pathology and the progressive clinical course of multiple sclerosis. Previous data has underlined the importance of CD4+ T cell involvement in mediating the autoimmune processes associated with the destruction of myelin and the role of the T helper 1 (Th1) pattern of cytokine secretion. However, EAE studies have also demonstrated that other cells involved in innate and/or adaptive immune responses may also play a critical role in the early and progressive events of the immune reaction leading to inflammation and CNS damage. In this review, we present such new data and discuss their potent implication for future new therapeutical approaches.
Assuntos
Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Células Matadoras Naturais/imunologia , Mastócitos/imunologia , Esclerose Múltipla/imunologia , Animais , Linfócitos B/imunologia , Humanos , CamundongosRESUMO
Muscle-invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murine bladder tumour cell line MB49 and its more aggressive variant MB49-I, we demonstrate that the adaptive immune system efficiently limits progression of MB49, whereas MB49-I has lost tumour antigens and is insensitive to adaptive immune responses. Furthermore, we unravel a parallel mechanism developed by MB49-I to subvert its environment: de novo secretion of the proteoglycan decorin. We show that decorin overexpression in the MB49/MB49-I model is required for efficient progression, by promoting angiogenesis and tumour cell invasiveness. Finally, we show that these results are relevant to muscle-invasive human bladder carcinomas, which overexpress decorin together with angiogenesis- and adhesion/migration-related genes, and that decorin overexpression in the human bladder carcinoma cell line TCCSUP is required for efficient invasiveness in vitro. We thus propose decorin as a new therapeutic target for these aggressive tumours.
Assuntos
Decorina/metabolismo , Imunidade Adaptativa , Animais , Linhagem Celular Tumoral , Movimento Celular , Citocinas/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Decorina/antagonistas & inibidores , Decorina/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologiaRESUMO
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune demyelinating diseases of the central nervous system (CNS). Interferon-gamma-producing Th1 and interleukin-17-producing Th17 CD4(+) T helper (Th) cells mediate disease pathogenesis in EAE and likely in MS as well. However, the relative contribution of each Th subset to autoimmune processes in the CNS remains unclear. Emerging data suggest that both Th1 and Th17 cells contribute to CNS autoimmunity, albeit through different mechanisms. A better understanding of the roles that Th1 and Th17 cells play in autoimmune inflammation will be helpful in developing new therapeutic approaches. In this review, we discuss recent findings on the roles of Th1 and Th17 cells in the pathogenesis of EAE.