RESUMO
Inflammation is an integral part of autoimmune diseases, which are caused by dysregulation of the immune system. This dysregulation involves an imbalance between pro-inflammatory versus anti-inflammatory mediators. These mediators include various cytokines and chemokines; defined subsets of T helper/T regulatory cells, M1/M2 macrophages, activating/tolerogenic dendritic cells, and antibody-producing/regulatory B cells. Despite the availability of many anti-inflammatory/immunomodulatory drugs, the severe adverse reactions associated with their long-term use and often their high costs are impediments in effectively controlling the disease process. Accordingly, suitable alternatives are being sought for these conventional drugs. Natural products offer promising adjuncts/alternatives in this regard. The availability of specific compounds isolated from dietary/medicinal plant extracts have permitted rigorous studies on their disease-modulating activities and the mechanisms involved therein. Here, we describe the basic characteristics, mechanisms of action, and preventive/therapeutic applications of 5 well-characterized natural product compounds (Resveratrol, Curcumin, Boswellic acids, Epigallocatechin-3-gallate, and Triptolide). These compounds have been tested extensively in animal models of autoimmunity as well as in limited clinical trials in patients having the corresponding diseases. We have focused our description on predominantly T cell-mediated diseases, such as rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, ulcerative colitis, and psoriasis.
Assuntos
Artrite Reumatoide , Doenças Autoimunes , Produtos Biológicos , Animais , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Inflamação , Artrite Reumatoide/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , MacrófagosRESUMO
Anti-drug antibody formation poses tremendous obstacles for optimal treatment of hemophilia A (HA). In this study, we sought to utilize chimeric receptor-modified natural regulatory T cells (Tregs) to target FVIII-specific memory B cells, which are responsible for persistent anti-FVIII neutralizing antibodies (inhibitors) in HA patients. Thus, CD4+CD25 hi CD304+ natural Tregs were FACS sorted from naïve C57BL/6 mice and retrovirally transduced to express a chimeric B-cell antibody receptor (BAR) containing the immunodominant A2 domain of FVIII. Plasmablast-depleted (CD138 neg ) splenocytes from FVIII immunized FVIII-knockout HA mice served as the source for FVIII-specific memory B cells, which were specifically stimulated in vitro with FVIII and enumerated in a B-cell ELISPOT assays. Adding A2-BAR Tregs (1 per 150 splenocytes), but not conventional T cells, to the CD138- splenocytes significantly suppressed the formation of anti-FVIII antibody secreting cells (ASC), compared to the non-relevant OVA-BAR Tregs control group. The observation that A2-BAR Tregs can suppress the response to FVIII suggests that bystander suppression can occur in the local milieu in this system. Transwell experiments confirmed that the suppression was contact-dependent. Moreover, even in the presence of antibodies to FVIII (so-called inhibitors), similarly prepared CD4+CD25 hi CD127 low A2-BAR human natural Tregs completely suppressed polyclonal anti-FVIII ASC formation. In conclusion, we demonstrated in vitro that FVIII domain-expressing BAR Tregs could efficiently target and suppress FVIII-specific memory B cells.
Assuntos
Linfócitos B/imunologia , Engenharia Celular/métodos , Fator VIII/imunologia , Fator VIII/farmacologia , Memória Imunológica/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Células Cultivadas , Fator VIII/genética , Feminino , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Imunização/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos Quiméricos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Transdução Genética/métodosRESUMO
Using phage peptide library screening, we identified peptide-encoding phages that selectively home to the inflamed central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis (MS). A phage peptide display library encoding cyclic 9-amino-acid random peptides was first screened ex-vivo for binding to the CNS tissue of EAE mice, followed by in vivo screening in the diseased mice. Phage insert sequences that were present at a higher frequency in the CNS of EAE mice than in the normal (control) mice were identified by DNA sequencing. One of the phages selected in this manner, denoted as MS-1, was shown to selectively recognize CNS tissue in EAE mice. Individually cloned phages with this insert preferentially homed to EAE CNS after an intravenous injection. Similarly, systemically-administered fluorescence-labeled synthetic MS-1 peptide showed selective accumulation in the spinal cord of EAE mice. We suggest that peptide MS-1 might be useful for targeted drug delivery to CNS in EAE/MS.
Assuntos
Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Peptídeos/metabolismo , Animais , Encéfalo/metabolismo , Biologia Computacional , Encefalomielite Autoimune Experimental/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Biblioteca de Peptídeos , Peptídeos/genética , Medula Espinal/metabolismoRESUMO
Allergy is a major public health concern, the main treatment for which is symptomatic relief with anti-inflammatory drugs. A key clinical challenge is to induce specific tolerance in order to control allergen-specific memory B and T cells, and specifically block effector cell responses. Our lab recently developed antigen-specific regulatory T-cell (Treg) therapies as a treatment for adverse responses. Recently, we created a chimeric antigen receptor (CAR) approach in which we engineered a target protein antigen, ovalbumin (OVA), linked with the transmembrane and signal transduction domains, CD28-CD3ζ to directly target B cells and sensitized mast cells in an allergy model. We named this receptor "BAR" for B-cell Antibody Receptor. Murine or human Tregs, transduced with a BAR containing OVA or control Tregs expressing an unrelated antigen, were successfully expanded in vitro and tested in the murine OVA-alum allergy model with measurable titers of anti-OVA IgE. Because BAR Tregs express the target antigen and could interact with specific IgE on sensitized mast cells, we first demonstrated that intravenously injected OVA-BAR Tregs did not directly lead to a drop in temperature or release of mediators in plasma indicative of anaphylaxis. Forty-eight hours later, mice were challenged intraperitoneally with 200⯵g OVA to induce an anaphylactic reaction, and temperature immediately measured for 30â¯min. We found that OVA-BAR Tregs protected mice from hypothermia, whereas mice given control BARs (expressing an unrelated antigen) or PBS showed substantial temperature drops indicative of anaphylaxis when systemically challenged with OVA. Importantly, this effect was also demonstrated in a passive anaphylaxis model in which mice that received anti-OVA IgE antibody were protected from hypothermia when treated with OVA-BAR Tregs prior to systemic OVA challenge. These results provide proof of principle that engineered allergen-specific T-regulatory cells can provide clinical protection against severe allergic reactions in individuals already IgE-sensitized to an allergen.
Assuntos
Anafilaxia/prevenção & controle , Ovalbumina/imunologia , Linfócitos T Reguladores/metabolismo , Alérgenos/imunologia , Animais , Feminino , Tolerância Imunológica/imunologia , Imunização Passiva , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Aim: Rheumatoid arthritis is an autoimmune disease affecting the joints. Antiarthritic drugs are given systemically, thereby exposing various healthy organs to these drugs, resulting in adverse reactions. Accordingly, there is an urgent need for targeted drug delivery methods for inflamed joints. Materials & methods: We developed a liposomal drug delivery system using a novel peptide ligand (CKPFDRALC) named ART-2, which homes to the inflamed joints when injected intravenously to rats with adjuvant-induced arthritis. Results: The ART-2-coated liposomes encapsulating an antiarthritic drug, dexamethasone (DEX), were more effective in inhibiting arthritis progression than control-DEX liposomes or free DEX, despite a comparable safety profile. Conclusion: Peptide-targeted therapy has advantages over conventional drug delivery and can be adapted for rheumatoid arthritis therapy.
Assuntos
Anti-Inflamatórios/química , Artrite Experimental/tratamento farmacológico , Dexametasona/química , Lipossomos/química , Peptídeos/química , Animais , Anti-Inflamatórios/farmacocinética , Sobrevivência Celular , Dexametasona/farmacocinética , Composição de Medicamentos/métodos , Células Endoteliais da Veia Umbilical Humana , Humanos , Articulações/metabolismo , Masculino , Terapia de Alvo Molecular/métodos , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Ratos , Ratos Endogâmicos Lew , Propriedades de Superfície , Distribuição TecidualRESUMO
OBJECTIVE AND DESIGN: Multiple sclerosis (MS) is a debilitating autoimmune disease involving immune dysregulation of the pathogenic T helper 17 (Th17) versus protective T regulatory (Treg) cell subsets, besides other cellular aberrations. Studies on the mechanisms underlying these changes have unraveled the involvement of mitogen-activated protein kinase (MAPK) pathway in the disease process. We describe here a gene expression- and bioinformatics-based study showing that celastrol, a natural triterpenoid, acting via MAPK pathway regulates the downstream genes encoding serum/glucocorticoid regulated kinase 1 (SGK1), which plays a vital role in Th17/Treg differentiation, and brain-derived neurotrophic factor (BDNF), which is a neurotrophic factor, thereby offering protection against experimental autoimmune encephalomyelitis (EAE) in mice. METHODS: We first tested the gene expression profile of splenocytes of EAE mice in response to the disease-related antigen, myelin oligodendrocyte glycoprotein (MOG), and then examined the effect of celastrol on that profile. RESULTS: Interestingly, celastrol reversed the expression of many MOG-induced genes involved in inflammation and immune pathology. The MAPK pathway involving p38MAPK and ERK was identified as one of the mediators of celastrol action. It involved suppression of SGK1 but upregulation of BDNF, which then contributed to protection against EAE. CONCLUSION: Our results not only provide novel insights into disease pathogenesis, but also offer promising therapeutic targets for MS.
Assuntos
Anti-Inflamatórios , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fatores Imunológicos , Triterpenos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Citocinas/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/imunologia , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/imunologia , Glicoproteína Mielina-Oligodendrócito , Triterpenos Pentacíclicos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Baço/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Triterpenos/farmacologia , Triterpenos/uso terapêuticoRESUMO
Multiple sclerosis (MS) is a debilitating autoimmune disease affecting over 2.3 million people worldwide, and it is characterized by inflammation and demyelination of nerve cells. The currently available biomarkers for the diagnosis and management of MS have inherent limitations, therefore, additional new biomarkers are needed. We studied the microRNA (miRNA) profile of splenocytes of mice having experimental autoimmune encephalomyelitis (EAE), a model of human MS. A miRNA-microarray analysis revealed increased expression of nine miRNAs (let-7e, miR-23b, miR-31, miR-99b, miR-125a, miR-146b, miR-155, miR-193b, and miR-221) following EAE development. Interestingly, serum levels of miR-99b, miR-125a, and miR-146b were significantly higher in EAE mice compared to normal mice. Bioinformatics analysis revealed the experimentally validated as well as predicted gene targets of specific miRNAs that are important for disease progression in MS. Specifically, we observed inverse correlation in the levels of miR-99b versus LIF, and between miR-125a versus BDNF and LIF. Our results suggest that above-mentioned miRNAs may play a crucial role in the pathogenesis of MS, and that miR-99b, miR-125a, and miR-146b in particular may serve as useful biomarkers for disease activity.
Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Biomarcadores/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial tissue of the joints. Inadequately controlled disease may cause severe joint damage and deformity. Currently, the anti-arthritic drugs are given systemically, and therefore, they are widely distributed to other organs that are not the intended therapeutic targets. Accordingly, using a particular dose/regimen of a drug to achieve an effective local concentration of the drug in arthritic joints may lead to expected adverse effects involving other organs. Thus, improved methods of drug delivery are needed for arthritis therapy. One attractive approach is the targeting of a systemically administered drug to the inflamed joints. We describe here a prototypic drug delivery system using a novel peptide ligand denoted as ART-1. We previously reported ART-1 (=ADK) as a peptide that preferentially homes to the inflamed joints of arthritic rats and binds to synovial endothelial cells. We tested the ART-1-coated liposomes encapsulating a fluorescent compound for binding to activated endothelial cells in vitro and homing to arthritic joints in vivo, compared to control liposomes lacking the ART-1 coating. Similar liposomes but encapsulating an immunomodulatory cytokine interleukin-27 (ART-1-IL-27 liposomes) were tested for their anti-arthritic activity compared with control liposomes. ART-1-displaying liposomes showed better binding to endothelial cells as well as in vivo homing to arthritic joints compared to control liposomes. Furthermore, ART-1-IL-27 liposomes, when intravenously injected to arthritic rats after the onset of arthritis, were more effective in suppressing disease progression than control-IL-27 liposomes lacking ART-1 or free IL-27 at an equivalent dose of IL-27. In addition, ART-1-directed liposomal IL-27 had a better safety profile than undirected liposomal IL-27 or free IL-27, thereby offering an improved therapeutic index for IL-27 therapy. These results provide a proof-of concept for the use of a novel joint-homing peptide for targeted delivery of drugs including biologics or small molecule compounds to arthritic joints with enhanced efficacy and reduced systemic exposure. This targeted therapy platform may be suitable for use in RA patients.
Assuntos
Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Fatores Imunológicos/administração & dosagem , Interleucinas/administração & dosagem , Lipossomos/metabolismo , Peptídeos/metabolismo , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Fatores Imunológicos/uso terapêutico , Interleucinas/uso terapêutico , Articulações/efeitos dos fármacos , Articulações/metabolismo , Articulações/patologia , Masculino , Ratos Endogâmicos LewRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints affecting about 0.3â»1% of the population in different countries. About 50â»60 percent of RA patients respond to presently used drugs. Moreover, the current biomarkers for RA have inherent limitations. Consequently, there is a need for additional, new biomarkers for monitoring disease activity and responsiveness to therapy of RA patients. We examined the micro-RNA (miRNA) profile of immune (lymphoid) cells of arthritic Lewis rats and arthritic rats treated with celastrol, a natural triterpenoid. Experimental and bioinformatics analyses revealed 8 miRNAs (miR-22, miR-27a, miR-96, miR-142, miR-223, miR-296, miR-298, and miR-451) and their target genes in functional pathways important for RA pathogenesis. Interestingly, 6 of them (miR-22, miR-27a, miR-96, miR-142, miR-223, and miR-296) were further modulated by celastrol treatment. Interestingly, serum levels of miR-142, miR-155, and miR-223 were higher in arthritic versus control rats, whereas miR-212 showed increased expression in celastrol-treated rats compared with arthritic rats or control rats. This is the first study on comprehensive miRNA expression profiling in the adjuvant-induced arthritis (AA) model and it also has revealed new miRNA targets for celastrol in arthritis. We suggest that subsets of the above miRNAs may serve as novel biomarkers of disease activity and therapeutic response in arthritis.
Assuntos
Artrite Reumatoide/sangue , Doenças Autoimunes/sangue , MicroRNAs/sangue , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Células Cultivadas , Masculino , Medicina Tradicional Chinesa , Triterpenos Pentacíclicos , Ratos , Triterpenos/uso terapêuticoRESUMO
Rheumatoid arthritis (RA) is a chronic, debilitating illness characterized by painful swelling of the joints, inflammation of the synovial lining of the joints, and damage to cartilage and bone. Several anti-inflammatory and disease-modifying drugs are available for RA therapy. However, the prolonged use of these drugs is associated with severe side effects. Furthermore, these drugs are effective only in a proportion of RA patients. Hence, there is a need to search for new therapeutic agents that are effective yet safe. Interestingly, a variety of herbs and other natural products offer a vast resource for such anti-arthritic agents. We discuss here the basic features of RA pathogenesis; the commonly used animal models of RA; the mainstream drugs used for RA; the use of well-characterized natural products possessing anti-arthritic activity; the application of nanoparticles for efficient delivery of such products; and the interplay between dietary products and the host microbiome for maintenance of health and disease induction. We believe that with several advances in the past decade in the characterization and functional studies of natural products, the stage is set for widespread clinical testing and/or use of these products for the treatment of RA and other diseases.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Artrite/imunologia , Doenças Autoimunes/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Artrite/etiologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Doenças Autoimunes/etiologia , Produtos Biológicos/farmacologia , Biomarcadores , Modelos Animais de Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , Mediadores da Inflamação/metabolismo , Microbiota , Terapia de Alvo Molecular , Nanopartículas/química , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêuticoRESUMO
Celastrol, a triterpenoid derived from traditional Chinese medicinal plants, has anti-inflammatory, antioxidant, and anticancer activities. Celastrol has shown preventive/therapeutic effects in experimental models of several chronic diseases. These include, chronic inflammatory and autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and psoriasis), neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis), atherosclerosis, obesity, Type 2 diabetes, and cancer. Celastrol modulates intricate cellular pathways and networks associated with disease pathology, and it interrupts or redirects the aberrant cellular and molecular events so as to limit disease progression and facilitate recovery, where feasible. The major cell signaling pathways modulated by celastrol include the NF-kB pathway, MAPK pathway, JAK/STAT pathway, PI3K/Akt/mTOR pathway, and antioxidant defense mechanisms. Furthermore, celastrol modulates cell proliferation, apoptosis, proteasome activity, heat-shock protein response, innate and adaptive immune responses, angiogenesis, and bone remodeling. Current understanding of the mechanisms of action of celastrol and information about its disease-modulating activities in experimental models have set the stage for testing celastrol in clinical studies as a therapeutic agent for several chronic human diseases.
Assuntos
Triterpenos/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Doenças Autoimunes/tratamento farmacológico , Doença Crônica , Humanos , Inflamação/tratamento farmacológico , Triterpenos Pentacíclicos , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologiaRESUMO
Elevated production of arachidonic acid (AA)-derived pro-inflammatory eicosanoids due to the concerted action of secretory phospholipase A2 group IIA (sPLA2IIA), 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) is a common feature of many inflammatory disorders. Hence, modulation of the bioactivity of these 3 enzymes is an important strategy to control inflammation. However, the failure of drugs specific for an individual enzyme (sPLA2IIA-, 5-LOX- or COX-2) and the success of 5-LOX/COX-2 dual inhibitors in effectively controlling inflammation in clinical trials prompted us to evaluate a common inhibitor for sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol, a quinone methide triterpene, was selected in this regard through molecular docking studies. We provide the first evidence for celastrol's ability to inhibit the catalytic activity of sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol significantly inhibited the catalytic activity of sPLA2IIA (IC50=6µM) in vitro, which is independent of substrate and calcium concentration. In addition, celastrol inhibited the catalytic activities of 5-LOX (IC50=5µM) and COX-2 (IC50=20µM) in vitro; sPLA2IIA-induced edema and carrageenan-induced edema in mice; and lipopolysaccharide-stimulated production of PGE2 in human neutrophils. Thus, celastrol modulates inflammatory responses by targeting multiple enzymes of AA pathway.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Ácido Araquidônico/metabolismo , Catálise/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Fosfolipases A2 do Grupo II/metabolismo , Inflamação/tratamento farmacológico , Triterpenos/farmacologia , Animais , Cálcio/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Edema/metabolismo , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Triterpenos PentacíclicosRESUMO
Celastrol is a bioactive compound derived from traditional Chinese medicinal herbs of the Celastraceae family. Celastrol is known to possess anti-inflammatory and anti-oxidant activities. Our studies have highlighted the immunomodulatory attributes of celastrol in adjuvant-induced arthritis (AA), an experimental model of human rheumatoid arthritis (RA). RA is an autoimmune disease characterized by chronic inflammation of the synovial lining of the joints, leading eventually to tissue damage and deformities. Identification of the molecular targets of celastrol such as the NF-κB pathway, MAPK pathway, JAK/STAT pathway and RANKL/OPG pathway has unraveled its strategic checkpoints in controlling arthritic inflammation and tissue damage in AA. The pathological events that are targeted and rectified by celastrol include increased production of pro-inflammatory cytokines; an imbalance between pathogenic T helper 17 and regulatory T cells; enhanced production of chemokines coupled with increased migration of immune cells into the joints; and increased release of mediators of osteoclastic bone damage. Accordingly, celastrol is a promising candidate for further testing in the clinic for RA therapy. Furthermore, the results of other preclinical studies suggest that celastrol might also be beneficial for the treatment of a few other autoimmune diseases besides arthritis.
Assuntos
Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Produtos Biológicos/farmacologia , Inflamação/etiologia , Inflamação/metabolismo , Triterpenos/farmacologia , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Autoimunidade/efeitos dos fármacos , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunomodulação/efeitos dos fármacos , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Triterpenos Pentacíclicos , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Triterpenos/química , Triterpenos/uso terapêuticoRESUMO
Interleukin-27 (IL-27) is a new member of the IL-12 family. It is produced by activated antigen-presenting cells and plays an important role in the regulation of CD4+ T cell differentiation and immune response. IL-27 activates multiple signaling cascades, including the JAK-STAT and p38 MAPK pathways. Several studies have revealed that IL-27 promotes the differentiation of Th1 and Tr1, but inhibits Th2, Th17, and Treg cells. However, a few studies have shown an opposite effect on certain T cell subsets, such as Treg. IL-27 displays both pro- and anti- inflammatory activities in different autoimmune diseases. Here, we have discussed the role of IL-27 in rheumatoid arthritis, multiple sclerosis, colitis, lupus, psoriasis, type 1 diabetes, and uveitis. Most of this information is derived from experimental models of these autoimmune diseases. The mechanistic basis of the dual role of IL-27 in inflammation and autoimmunity is still not fully defined. In general, the pro-/anti-inflammatory activity of IL-27 is influenced by the underlying immune effector pathways, the phase of the disease, the presence or absence of counter-regulatory cytokines/T cell subsets, and the tissue/cell type under study. Despite a spectrum of outcomes in various autoimmune diseases, mostly anti-inflammatory and immunomodulatory effects of IL-27 have been observed in this category of diseases. Accordingly, IL-27 represents a novel, promising target/agent for the treatment of autoimmune diseases.
Assuntos
Autoimunidade , Interleucina-27/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Humanos , Ativação LinfocitáriaRESUMO
Inflammation is an integral component of autoimmune arthritis. The balance of pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells can influence disease severity, and its resetting offers an attractive approach to control autoimmunity. We determined the frequency of Th17 and Treg in the joints of rats with adjuvant arthritis (AA), a model of rheumatoid arthritis (RA). We also investigated the impact of Celastrol, a bioactive compound from the traditional Chinese medicine Celastrus that can suppress AA, on Th17/Treg balance in the joints. Celastrol treatment reduced Th17 cells but increased Treg in the joints, and it inhibited Th17 differentiation but promoted Treg differentiation in vitro by blocking the activation of pSTAT3. Furthermore, Celastrol limited the production of Th17-differentiating cytokines and chemokines (CCL3, CCL5). Thus, Celastrol suppressed arthritis in part by altering Th17/Treg ratio in inflamed joints, and it should be tested as a potential adjunct/alternative for RA therapy.
Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide , Diferenciação Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Doenças Autoimunes/imunologia , Quimiotaxia/imunologia , Modelos Animais de Doenças , Inflamação/imunologia , Triterpenos Pentacíclicos , Ratos , Linfócitos T Reguladores/imunologia , Células Th17/imunologiaRESUMO
The T helper (Th) cell subsets are characterized by the type of cytokines produced and the master transcription factor expressed. Th1 cells participate in cell-mediated immunity, whereas Th2 cells promote humoral immunity. Furthermore, the two subsets can control each other. Thereby, Th1-Th2 balance offered a key paradigm in understanding the induction and regulation of immune pathology in autoimmune and other diseases. However, over the past decade, Th17 cells producing interleukin-17 (IL-17) have emerged as the major pathogenic T cell subset in many pathological conditions that were previously attributed to Th1 cells. In addition, the role of CD4+CD25+T regulatory cells (Treg) in controlling the activity of Th17 and other T cell subsets has increasingly been realized. Thereby, examination of the Th17/Treg balance in the course of autoimmune diseases has significantly advanced our understanding of the pathogenesis of these disorders. The differentiation of Th17 and Treg cells from naïve T cells is inter-related and controlled in part by the cytokine milieu. For example, transforming growth factor ß (TGFß) is required for Treg induction, whereas the same cytokine in the presence of IL-6 (or IL-1) promotes the differentiation of Th17. Furthermore, IL-23 plays a role in the maintenance of Th17. Accordingly, novel therapeutic approaches are being developed to target IL-23/IL-17 as well as to modulate the Th17/Treg balance in favor of immune regulation to control autoimmunity.
Assuntos
Artrite Reumatoide/imunologia , Artrite/imunologia , Doenças Autoimunes/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Artrite/fisiopatologia , Artrite/terapia , Artrite Experimental/imunologia , Artrite Experimental/fisiopatologia , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/terapia , Doenças Autoimunes/fisiopatologia , Doenças Autoimunes/terapia , Humanos , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Linfócitos T Reguladores/patologia , Equilíbrio Th1-Th2 , Células Th17/patologiaRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting the synovial joints. The currently available drugs for RA are effective only in a proportion of patients and their prolonged use is associated with severe adverse effects. Thus, new anti-arthritic agents are being sought. We tested Pristimerin, a naturally occurring triterpenoid, for its therapeutic activity against rat adjuvant arthritis. Pristimerin effectively inhibited both arthritic inflammation and cartilage and bone damage in the joints. Pristimerin-treated rats exhibited a reduction in the pro-inflammatory cytokines (IL-6, IL-17, IL-18, and IL-23) and the IL-6/IL-17-associated transcription factors (pSTAT3 and ROR-γt), coupled with an increase in the immunomodulatory cytokine IL-10. Also increased was IFN-γ, which can inhibit IL-17 response. In addition, the Th17/Treg ratio was altered in favor of immune suppression and the RANKL/OPG ratio was skewed towards anti-osteoclastogenesis. This is the first report on testing Pristimerin in arthritis. We suggest further evaluation of Pristimerin in RA patients.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite/imunologia , Artrite/metabolismo , Doenças Autoimunes , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Artrite/tratamento farmacológico , Artrite/patologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/imunologia , Modelos Animais de Doenças , Progressão da Doença , Contagem de Linfócitos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Triterpenos Pentacíclicos , Ratos , Fator de Transcrição STAT3/metabolismo , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Triterpenos/administração & dosagemRESUMO
Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases. Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage. The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA). For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA. The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling. Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity. Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities. Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect. Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Citocinas/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/genética , Terapia Genética , Humanos , Imunossupressores/uso terapêutico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune origin. Huo-luo-xiao-ling dan (HLXL) is an herbal mixture that has been used in traditional Chinese medicine over several decades to treat chronic inflammatory diseases including RA. However, the mechanism of the anti-arthritic action of this herbal remedy is poorly understood at the molecular level. In this study, we determined by microarray analysis the effects of HLXL on the global gene expression profile of the draining lymph node cells (LNC) in the rat adjuvant arthritis (AA) model of human RA. In LNC restimulated in vitro with the disease-related antigen mycobacterial heat-shock protein 65 (Bhsp65), 84 differentially expressed genes (DEG) (64 upregulated and 20 downregulated) versus 120 DEG (94 upregulated and 26 downregulated) were identified in HLXL-treated versus vehicle (Water)-treated rats, respectively, and 62 DEG (45 upregulated and 17 downregulated) were shared between the two groups. The most affected pathways in response to HLXL treatment included immune response, inflammation, cellular proliferation and apoptosis, and metabolic processes, many of which are directly relevant to arthritis pathogenesis. These results would advance our understanding of the mechanisms underlying the anti-arthritic activity of HLXL.
RESUMO
Susceptibility to autoimmunity is determined by multiple factors. Defining the contribution of the quantitative versus qualitative aspects of antigen-directed immune responses as well as the factors influencing target organ susceptibility is vital to advancing the understanding of the pathogenesis of autoimmunity. In a series of studies, we have addressed these issues using the adjuvant-induced arthritis (AA) model of human rheumatoid arthritis (RA). Lewis rats are susceptible to AA following immunization with heat-killed Mycobacterium tuberculosis H37Ra, whereas Wistar-Kyoto (WKY) rats of the same MHC (major histocompatibility complex) haplotype are resistant. Comparative studies on these and other susceptible/resistant rodent strains have offered interesting insights into differential cytokine responses in the face of comparable T cell proliferative response to the disease relevant antigens. Study of the cytokine kinetics have also permitted validation of the disease-protective versus disease-aggravating effects of specific cytokines by treatment of rats/mice with those cytokines at different phases of the disease. In regard to the target organ attributes, the migration of arthritogenic leukocytes into the joints; the expression of mediators of inflammation, angiogenesis, and tissue damage; the role of vascular permeability; and the characteristics of vascular endothelial cells have been examined. Further, various inhibitors of angiogenesis are effective in suppressing arthritis. Taken together, the differential cytokine responses and unique attributes of the target organ have revealed novel aspects of disease susceptibility and joint damage in AA. The translation of this basic research in animal models to RA patients would not only advance our understanding of the disease process, but also offer novel avenues for immunomodulation of this disease.