RESUMO
Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31-/- mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-ß1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1f/f CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-ß-IL-31 axis with implications for treatment of wound itching.
Assuntos
Interleucinas/metabolismo , Células de Langerhans/fisiologia , Prurido/patologia , Células Receptoras Sensoriais/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Feminino , Humanos , Interleucinas/genética , Células de Langerhans/transplante , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Receptores de Interleucina/metabolismo , Pele/citologia , Pele/crescimento & desenvolvimento , Pele/lesões , Canais de Cátion TRPV/metabolismo , Cicatrização/fisiologiaRESUMO
Diet has been suggested to be a potential environmental risk factor for the increasing incidence of autoimmune diseases, yet the underlying mechanisms remain elusive. Here, we show that high glucose intake exacerbated autoimmunity in mouse models of colitis and experimental autoimmune encephalomyelitis (EAE). We elucidated that high amounts of glucose specifically promoted T helper-17 (Th17) cell differentiation by activating transforming growth factor-ß (TGF-ß) from its latent form through upregulation of reactive oxygen species (ROS) in T cells. We further determined that mitochondrial ROS (mtROS) are key for high glucose-induced TGF-ß activation and Th17 cell generation. We have thus revealed a previously unrecognized mechanism underlying the adverse effects of high glucose intake in the pathogenesis of autoimmunity and inflammation.
Assuntos
Ingestão de Alimentos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Glucose/metabolismo , Mitocôndrias/metabolismo , Esclerose Múltipla/imunologia , Células Th17/imunologia , Animais , Autoimunidade , Diferenciação Celular , Células Cultivadas , Dieta , Modelos Animais de Doenças , Humanos , Inflamação , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
The molecular mechanisms by which signaling via transforming growth factor-ß (TGF-ß) and interleukin 4 (IL-4) control the differentiation of CD4(+) IL-9-producing helper T cells (TH9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated TH9 differentiation, as deletion of Id3 increased IL-9 production from CD4(+) T cells. Mechanistically, TGF-ß1 and IL-4 downregulated Id3 expression, and this process required the kinase TAK1. A reduction in Id3 expression enhanced binding of the transcription factors E2A and GATA-3 to the Il9 promoter region, which promoted Il9 transcription. Notably, Id3-mediated control of TH9 differentiation regulated anti-tumor immunity in an experimental melanoma-bearing model in vivo and also in human CD4(+) T cells in vitro. Thus, our study reveals a previously unrecognized TAK1-Id3-E2A-GATA-3 pathway that regulates TH9 differentiation.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteínas Inibidoras de Diferenciação/imunologia , Interleucina-9/biossíntese , Proteínas de Neoplasias/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Citometria de Fluxo , Humanos , Proteínas Inibidoras de Diferenciação/genética , Interleucina-9/imunologia , Camundongos , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , Transdução de Sinais/imunologiaRESUMO
Regulatory T cells (Treg cells) perform suppressive functions in disparate tissue environments and against many inflammatory insults, yet the tissue-enriched factor(s) that influence Treg cell phenotype and function remain largely unknown. We have shown a vital role for transforming growth factor-ß (TGF-ß) signals in safe-guarding specific Treg cell functions. TGF-ß signals were dispensable for steady-state Treg cell homeostasis and for Treg cell suppression of T cell proliferation and T helper-1 (Th1) cell differentiation. However, Treg cells require TGF-ß signals to appropriately dampen Th17 cells and regulate responses in the gastrointestinal tract. TGF-ß signaling maintains CD103 expression, promotes expression of the colon-specific trafficking molecule GPR15, and inhibits expression of GPR174, a receptor for lysophosphatidylserine, on Treg cells, collectively supporting the accumulation and retention of Treg cells in the colon and control of colitogenic responses. Thus, we reveal an unrecognized function for TGF-ß signaling as an upstream factor controlling Treg cell activity in specific tissue environments.
Assuntos
Especificidade de Órgãos/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Proliferação de Células , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Homeostase/imunologia , Cadeias alfa de Integrinas/imunologia , Cadeias alfa de Integrinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores Acoplados a Proteínas G/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
γδ intestinal intraepithelial lymphocytes (IELs) constitute the majority of IELs with unique CD8αα+ homodimers that are distinct from γδT cells in other tissues. However, it remains largely unclear how those cells develop. Here we show that transforming growth factor beta (TGF-ß) signaling controls the development of TCRγδ+CD8αα+ IELs. Deletion of TGF-ß receptors or Smad3 and Smad2 in bone marrow stem cells caused a deficiency of TCRγδ+CD8αα+ IELs in mixed bone marrow chimeric mice. Mechanistically, TGF-ß is required for the development of TCRγδ+CD8αα+ IELs thymic precursors (CD44-CD25- γδ thymocytes). In addition, TGF-ß signaling induced CD8α in thymic γδT cells and maintained CD8α expression and survival in TCRγδ+CD8αα+ IELs. Moreover, TGF-ß also indirectly controls TCRγδ+CD8αα+ IELs by modulating the function of intestinal epithelial cells (IECs). Importantly, TGF-ß signaling in TCRγδ+CD8αα+ IELs safeguarded the integrity of the intestinal barrier in dextran sulfate sodium (DSS)-induced colitis.
RESUMO
Prostate cancer is generally considered an immunologically "cold" tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent antitumor immune response to "heat up" the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-ß type II receptor, bolstering its activity in the TGF-ß-rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-ß-rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2-expressing cancer cell line-derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy.
Assuntos
Neoplasias da Próstata , Receptores de Antígenos Quiméricos , Masculino , Humanos , Camundongos , Animais , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva , Neoplasias da Próstata/patologia , Linfócitos T , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Microambiente Tumoral , Oxirredutases/metabolismoRESUMO
Interleukin-9 (IL-9)-producing CD4+ T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-ß), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-ß and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser213) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser213. Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.
Assuntos
Interleucina-4 , Interleucina-9 , Animais , Humanos , Camundongos , Diferenciação Celular/genética , Interleucina-4/metabolismo , Proteínas Repressoras/genética , RNA Interferente Pequeno/metabolismo , Serina/metabolismo , Linfócitos T Auxiliares-Indutores , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento Transformadores/metabolismoRESUMO
Adipose-derived mesenchymal stromal cells (ADSCs) play important roles in the alleviation of inflammation and autoimmune diseases. Interleukin-33 (IL-33), a member of the IL-1 family, has been shown to regulate innate and adaptive immunity. However, it is still unknown whether ADSCs regulate immune responses via IL-33. We show here that ADSCs produced IL-33 in response to IL-1ß stimulation, which depended on TAK1, ERK, and p38 pathways. ADSCs-derived IL-33 drove the proliferation of CD4+Foxp3+ST2+ regulatory T cells (Tregs) and alleviated experimental autoimmune Sjögren syndrome in mice. Importantly, human ADSCs also produced IL-33 in response to IL-1ß. Thus, we have revealed a previously unrecognized immunoregulatory function of ADSCs by IL-33 production in experimental autoimmunity, which may have clinical applications for human immunopathology.
RESUMO
Immune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (TH 1) responses and regulatory T (Treg ) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of TH 1:Treg cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of TH 1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by Treg cells. Importantly, interferon (IFN) -γ and tumor necrosis factor (TNF) -α cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized Treg cell deficiency-mediated TH 1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.
Assuntos
Apoptose , Células da Granulosa/patologia , Insuficiência Ovariana Primária/patologia , Esteroides/biossíntese , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Adulto , Animais , Feminino , Células da Granulosa/imunologia , Células da Granulosa/metabolismo , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
TCRαß+CD8αα+ intraepithelial lymphocytes (IELs) are abundant in gastrointestinal (GI) tract and play an important role in regulation of mucosal immunity and tolerance in the gut. However, it is unknown whether TCRαß+CD8αα+ IELs exist in the oral mucosa and if yes, what controls their development. We here identified and characterized TCRαß+CD8αα+ IELs from the murine oral mucosa. We showed that the number and function of TCRαß+CD8αα+ IELs were regulated by TGF-ß. We further revealed that oral TCRαß+CD8αα+ IELs could be altered under systemic inflammatory conditions and by antibiotic treatment at the neonatal age of the mice. Our findings have revealed a previously unrecognized population of oral IELs that may regulate oral mucosal immune responses.
Assuntos
Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas , Linfócitos Intraepiteliais/imunologia , Mucosa Bucal/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Animais , Animais Recém-Nascidos , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Microbioma Gastrointestinal , Imunidade nas Mucosas/efeitos dos fármacos , Interferon gama/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Linfócitos Intraepiteliais/efeitos dos fármacos , Linfócitos Intraepiteliais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/metabolismo , Fenótipo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The molecular pathways underlying the development of innate lymphoid cells (ILCs) are mostly unknown. Here we show that TGF-ß signaling programs the development of ILC2s from their progenitors. Specifically, the deficiency of TGF-ß receptor II in bone marrow progenitors results in inefficient development of ILC2s, but not ILC1s or ILC3s. Mechanistically, TGF-ß signaling is required for the generation and maintenance of ILC2 progenitors (ILC2p). In addition, TGF-ß upregulates the expression of the IL-33 receptor gene Il1rl1 (encoding IL-1 receptor-like 1, also known as ST2) in ILC2p and common helper-like innate lymphoid progenitors (CHILP), at least partially through the MEK-dependent pathway. These findings identify a function of TGF-ß in the development of ILC2s from their progenitors.
Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Diferenciação Celular , Imunidade Inata , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Interleucina-33/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/imunologia , Células-Tronco/citologia , Células-Tronco/imunologiaRESUMO
The clearance of apoptotic cells is an essential process to maintain homeostasis of immune system, which is regulated by immunoregulatory cytokines such as TGFß. We show here that Extracellular Vesicles (EVs) were highly released from apoptotic cells, and contributed to macrophage production of TGFß in vitro and in vivo. We further elucidated mechanistically that phosphatidylserine in EVs was a key triggering-factor, and transcription factor FOXO3 was a critical mediator for apoptotic EV-induced TGFß in macrophages. Importantly, we found that macrophages pre-exposed to EVs exhibited an anti-inflammatory phenotype. More strikingly, administration of EVs in vivo promotes Tregs differentiation and suppresses Th1 cell response, and ameliorates experimental colitis. Thus, apoptotic-EV-based treatment might be a promising therapeutic approach for human autoimmune disease.
Assuntos
Colite/patologia , Vesículas Extracelulares/metabolismo , Macrófagos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/efeitos da radiação , Colite/terapia , Modelos Animais de Doenças , Vesículas Extracelulares/transplante , Proteína Forkhead Box O3/antagonistas & inibidores , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Raios gama , Proteínas de Homeodomínio/genética , Humanos , Células Jurkat , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilserinas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timócitos/efeitos da radiação , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND: Clinical trials on multiple sclerosis with repeated injections of monoclonal antibodies depleting CD4+ T cells have not resulted in much success as a disease therapy. Here, we developed an immunotherapy for EAE in mice by combining a transient depletion of T cells together with the administration of neuron derived peptides. METHODS: EAE was induced in SJL and C57BL/6 mice, by proteolipid protein peptide PLP139-151 (pPLP) and myelin-oligodendrocyte glycoprotein MOG35-55 (pMOG) peptides, respectively. Anti-CD4 and anti-CD8 antibody were injected intraperitoneally before or after peptide immunization. EAE scores were evaluated and histology data from brain and spinal cord were analyzed. Splenocytes were isolated and CD4+, CD4+CD25- and CD4+CD25+ T cells were purified and cultured in the presence of either specific peptides or anti-CD3 antibody and proliferation of T cells as well as cytokines in supernatant were assessed. FINDINGS: This experimental treatment exhibited therapeutic effects on mice with established EAE in pPLP-susceptible SJL mice and pMOG-susceptible C57BL/6 mice. Mechanistically, we revealed that antibody-induced apoptotic T cells triggered macrophages to produce TGFß, and together with administered auto-antigenic peptides, generated antigen-specific Foxp3+ regulatory T cells (Treg cells) in vivo. INTERPRETATION: We successfully developed a specific immunotherapy to EAE by generating autoantigen-specific Treg cells. These findings have overcome the drawbacks of long and repeated depletion of CD4+ T cells, but also obtained long-term immune tolerance, which should have clinical implications for the development of a new effective therapy for multiple sclerosis. FUND: This research was supported by the Intramural Research Program of the NIH, NIDCR.
Assuntos
Apoptose/efeitos dos fármacos , Apoptose/imunologia , Autoantígenos/administração & dosagem , Encefalomielite Autoimune Experimental/imunologia , Peptídeos/administração & dosagem , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Autoantígenos/imunologia , Biomarcadores/metabolismo , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Feminino , Tolerância Imunológica , Fatores Imunológicos , Imunoterapia , Ativação Linfocitária , Camundongos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Peptídeos/imunologia , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Fagócitos/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do TratamentoRESUMO
Mucosal immunization by inactivated viruses often fails to evoke a sufficient immune response. Intensive efforts have been made to enhance the response by suitable adjuvants. We used the G+ nonpathogenic delipidated bacterium Bacillus firmus with pronounced immunostimulatory properties as an adjuvant for immunizing mice with inactivated influenza virus type A. BALB/c mice were immunized intratracheally with inactivated influenza A H1N1 and H3N2 viruses. The production of antibodies in sera and secretions was determined by the ELISA. The local situation in the lungs was assessed histologically and by testing the cytokine expression. The protective and cross-protective effect against infection was tested in in vivo experiments after infection with influenza virus A H1N1. B. firmus as adjuvant increased both systemic and mucosal antibody responses, improved protection against homologous virus and induced cross-protection against virus H1N1 after immunization with virus H3N2.
Assuntos
Adjuvantes Imunológicos , Anticorpos Antivirais/imunologia , Bacillus/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Animais , Anticorpos Antivirais/sangue , Reações Cruzadas , Citocinas/biossíntese , Citocinas/imunologia , Feminino , Humanos , Imunidade nas Mucosas , Imunização , Influenza Humana/mortalidade , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/prevenção & controleRESUMO
D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-ß activation, which in turn was mediated by upregulation of integrin αvß8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.
Assuntos
Colite/imunologia , Diabetes Mellitus Tipo 1/imunologia , Pneumopatias/imunologia , Pulmão/efeitos dos fármacos , Manose/farmacologia , Pâncreas/efeitos dos fármacos , Hipersensibilidade Respiratória/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Transferência Adotiva , Animais , Colo/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Técnicas In Vitro , Inflamação , Integrinas/efeitos dos fármacos , Integrinas/imunologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Pulmão/imunologia , Pneumopatias/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Ovalbumina/efeitos adversos , Oxirredução/efeitos dos fármacos , Pâncreas/imunologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Hipersensibilidade Respiratória/induzido quimicamente , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/imunologia , Regulação para CimaRESUMO
CD4(+)CD25(+)Foxp3(+)regulatory T cells (Treg cells) are extremely important in maintaining immune tolerance. Manipulation of Treg cells, especially autoantigen-specific Treg cells is a promising approach for treatments of autoimmune disease since Treg cells may provide the advantage of antigen specificity without overall immune suppression. However, the clinical application of Treg cells has long been limited due to low numbers of Treg cells and the difficulty in identifying their antigen specificity. In this review, we summarize studies that demonstrate regression of autoimmune diseases using Treg cells as therapeutics. We also discuss approaches to generate polyclonal and autoantigen-specific Treg cells in vitro and in vivo. We also discuss our recent study that describes a novel approach of generating autoantigen-specific Treg cells in vivo and restoring immune tolerance by two steps apoptosis-antigen therapy.
Assuntos
Doenças Autoimunes/terapia , Imunoterapia Adotiva , Linfócitos T Reguladores/imunologia , Animais , Apoptose , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfócitos T Reguladores/transplanteRESUMO
Psoriasis is an inflammatory skin disease affecting â¼2% of the world's population, but the aetiology remains incompletely understood. Recently, microbiota have been shown to differentially regulate the development of autoimmune diseases, but their influence on psoriasis is incompletely understood. We show here that adult mice treated with antibiotics that target Gram-negative and Gram-positive bacteria develop ameliorated psoriasiform dermatitis induced by imiquimod, with decreased pro-inflammatory IL-17- and IL-22-producing T cells. Surprisingly, mice treated neonatally with these antibiotics develop exacerbated psoriasis induced by imiquimod or recombinant IL-23 injection when challenged as adults, with increased IL-22-producing γδ(+) T cells. 16S rRNA gene compositional analysis reveals that neonatal antibiotic-treatment dysregulates gut and skin microbiota in adults, which is associated with increased susceptibility to experimental psoriasis. This link between neonatal antibiotic-mediated imbalance in microbiota and development of experimental psoriasis provides precedence for further investigation of its specific aetiology as it relates to human psoriasis.
Assuntos
Antibacterianos/efeitos adversos , Microbiota/efeitos dos fármacos , Polimixina B/efeitos adversos , Psoríase/induzido quimicamente , Vancomicina/efeitos adversos , Aminoquinolinas , Animais , Animais Recém-Nascidos , Suscetibilidade a Doenças , Interações Medicamentosas , Imiquimode , Interleucina-17/metabolismo , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Pele/imunologia , Linfócitos T/metabolismo , Interleucina 22RESUMO
Harnessing regulatory T (Treg) cells is a promising approach for treating autoimmune disease. However, inducing antigen-specific Treg cells that target inflammatory immune cells without compromising beneficial immune responses has remained an unmet challenge. We developed a pathway to generate autoantigen-specific Treg cells in vivo, which showed therapeutic effects on experimental autoimmune encephalomyelitis and nonobese diabetes in mice. Specifically, we induced apoptosis of immune cells by systemic sublethal irradiation or depleted B and CD8(+) T cells with specific antibodies and then administered autoantigenic peptides in mice with established autoimmune diseases. We demonstrated mechanistically that apoptotic cells triggered professional phagocytes to produce transforming growth factor-ß, under which the autoantigenic peptides directed naïve CD4(+) T cells to differentiate into Foxp3(+) Treg cells instead of into T effector cells in vivo. These antigen-specific Treg cells specifically ameliorated autoimmunity without compromising immune responses to bacterial antigen. We have thus successfully generated antigen-specific Treg cells with therapeutic activity toward autoimmunity. The findings may lead to the development of antigen-specific Treg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases.
Assuntos
Doenças Autoimunes/terapia , Bactérias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/imunologia , Depleção Linfocítica , CamundongosRESUMO
Mucosal immunization with non-living antigens usually requires the use of an adjuvant. The adjuvant activity of Bacillus firmus in the mucosal immunization of mice was described by our laboratory previously. In the present study, subcellular localization of B. firmus activities was followed. After mechanical disintegration, subcellular components of bacterium were fractionated by differential centrifugation and salting out. Bacterial cell walls, cytoplasmic membrane fraction, soluble cytoplasmic proteins, and ribosomal fractions were isolated. Their effect on the mouse immune system was studied. Lymphocyte proliferation and immunoglobulin formation in vitro were stimulated by bacterial cell wall (BCW), cytoplasmic membrane (CMF), and ribosomal fractions. BCW and CMF increased antibody formation after intratracheal immunization of mice with influenza A and B viruses, and increased protection against subsequent infection with influenza virus. The BCW fraction even induced intersubtypic cross-protection: Mice immunized with A/California/7/04 (H3N2) + BCW were resistant to the infection by the highly pathogenic A/PR/8/34 (H1N1) virus.