RESUMO
Programmed Cell Death 1 (PD-1) receptor and its ligands (PD-Ls) are essential to maintain peripheral immune tolerance and to avoid tissue damage. Consequently, altered gene or protein expression of this system of co-inhibitory molecules has been involved in the development of cancer and autoimmunity. Substantial progress has been achieved in the study of the PD-1/PD-Ls system in terms of regulatory mechanisms and therapy. However, the role of the PD-1/PD-Ls pathway in neuroinflammation has been less explored despite being a potential target of treatment for neurodegenerative diseases. Multiple Sclerosis (MS) is the most prevalent, chronic, inflammatory, and autoimmune disease of the central nervous system that leads to demyelination and axonal damage in young adults. Recent studies have highlighted the key role of the PD-1/PD-Ls pathway in inducing a neuroprotective response and restraining T cell activation and neurodegeneration in MS. In this review, we outline the molecular and cellular mechanisms regulating gene expression, protein synthesis and traffic of PD-1/PD-Ls as well as relevant processes that control PD-1/PD-Ls engagement in the immunological synapse between antigen-presenting cells and T cells. Also, we highlight the most recent findings regarding the role of the PD-1/PD-Ls pathway in MS and its murine model, experimental autoimmune encephalomyelitis (EAE), including the contribution of PD-1 expressing follicular helper T (TFH) cells in the pathogenesis of these diseases. In addition, we compare and contrast results found in MS and EAE with evidence reported in other autoimmune diseases and their experimental models, and review PD-1/PD-Ls-targeting therapeutic approaches.
Assuntos
Antígeno B7-H1/fisiologia , Esclerose Múltipla/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/fisiologia , Receptor de Morte Celular Programada 1/fisiologia , Animais , Antígeno B7-H1/química , Antígeno B7-H1/genética , Encéfalo/patologia , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica , Humanos , Sinapses Imunológicas , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/etiologia , Proteína 2 Ligante de Morte Celular Programada 1/química , Proteína 2 Ligante de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/química , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais/fisiologia , Células T Auxiliares Foliculares/imunologiaRESUMO
The recent success of PD-1 and PD-L1 blockade in cancer therapy illustrates the important role of the PD-1/PD-L1 pathway in the regulation of antitumor immune responses. However, signaling regulated by the PD-1/PD-L pathway is also associated with substantial inflammatory effects that can resemble those in autoimmune responses, chronic infection, and sepsis, consistent with the role of this pathway in balancing protective immunity and immunopathology, as well as in homeostasis and tolerance. Targeting PD-1/PD-L1 to treat cancer has shown benefits in many patients, suggesting a promising opportunity to target this pathway in autoimmune and inflammatory disorders. Here, we systematically evaluate the diverse biological functions of the PD-1/PD-L pathway in immune-mediated diseases and the relevant mechanisms that control these immune reactions.
Assuntos
Antígeno B7-H1/fisiologia , Neoplasias/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/fisiologia , Receptor de Morte Celular Programada 1/fisiologia , Animais , Autoimunidade , Antígeno B7-H1/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Humanos , Infecções/imunologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sepse/imunologia , Transdução de Sinais/fisiologiaRESUMO
Multiple sclerosis (MS) is an inflammatory demyelinating disease of CNS. Astragalus polysaccharides (APS), the main active extract from astragalus membranaceus which is a kind of traditional Chinese medicinal herb, is associated with a variety of immunomodulatory activities. We have evaluated the therapeutic effects of APS in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). It was found that APS could effectively alleviate EAE through inhibiting MOG35-55-specific T cell proliferation and reducing the expression of proinflammatory cytokines, which is mediated by up-regulating the expression of PD-1/PD-Ls signaling pathway. Our results demonstrated that EAE could be suppressed significantly by APS administration. It indicated that APS might be a potential of developing innovative drug for the therapy of MS.
Assuntos
Anti-Inflamatórios/uso terapêutico , Astragalus propinquus/química , Antígeno B7-H1/biossíntese , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fitoterapia , Gomas Vegetais/uso terapêutico , Proteína 2 Ligante de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/biossíntese , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Antígeno B7-H1/genética , Antígeno B7-H1/fisiologia , Citocinas/biossíntese , Citocinas/genética , Encefalomielite Autoimune Experimental/induzido quimicamente , Feminino , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , Gomas Vegetais/farmacologia , Proteína 2 Ligante de Morte Celular Programada 1/genética , Proteína 2 Ligante de Morte Celular Programada 1/fisiologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Regulação para Cima/efeitos dos fármacosRESUMO
Influenza viruses can bring about acute respiratory diseases and are a potential hazard to human health. Antiviral drugs are the main ways to control the influenza virus infection except the vaccine. In this study, the immune regulation activity of pterodontic acid isolated from Laggera pterodonta induced by influenza A virus in vitro was evaluated. In studies on anti-influenza activity, our results showed that it maybe target the influenza protein of polymerase basic 1 (PB1), polymerase basic 2 (PB2), polymerase acid (PA), nuclear protein (NP), non-structural protein (NS), and matrix protein (M) but not hemagglutinin (HA) and neuraminidase (NA). In studies on immune regulation, our results demonstrated that pterodontic acid can inhibit the Retinoic acid inducible gene-I (RIG-I) expression in mRNA and protein level at 100 µg/ml, then further to clarify its action on the signalling pathway, The results indicated that pterodontic acid can inhibit the Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Fas Ligand (TRAIL/Fasl) expression in mRNA level at 100 µg/ml; the cleaved caspase 3/7, p-NF-KB, and p-ERK were all suppressed in protein level by pterodontic acid at 100 µg/ml. This confirmed its mechanism that restrained the nuclear export of viral RNPs. The interferon system was also affected, the STAT1, IFN-α, IFN-ß expression were also inhibited by pterodontic acid at 25-100 µg/ml and also, the important programmed death-ligand of PD-L1 and PD-L2 was inhibited at 50-100 µg/ml. The mechanisms of pterodontic acid against influenza virus infection may be a cascade inhibition and it has the anti-inflammatory activity, which has no side effect, and can be as a supplement drug in clinical influenza virus infection.
Assuntos
Antivirais/farmacologia , Asteraceae/química , Antígeno B7-H1/fisiologia , Proteína DEAD-box 58/antagonistas & inibidores , Vírus da Influenza A/efeitos dos fármacos , Interferon Tipo I/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Proteína 2 Ligante de Morte Celular Programada 1/antagonistas & inibidores , Sesquiterpenos/farmacologia , Células A549 , Antígeno B7-H1/antagonistas & inibidores , Humanos , Vírus da Influenza A/fisiologia , Proteína 2 Ligante de Morte Celular Programada 1/fisiologia , Receptores Imunológicos , Ribonucleoproteínas/metabolismo , Fator de Transcrição STAT1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidoresRESUMO
Tumor cells evade immune destruction, at least partially, by upregulating inhibitory signals to limit effector T cell activation. Programmed death 1 (PD-1) is one of the most critical co-inhibitory molecules limiting the T-cell antitumor response. PD-1 and its ligands, PD-L1 and PD-L2, are overexpressed by various types of tumors as well as reactive cells in the tumor microenvironment. A growing body of evidence has shown the clinical efficiency and minimal toxicity of PD-1 pathway inhibitors in patients with solid tumors, but the role of these inhibitors in lymphoid malignancies is much less well studied. In this review, we analyze the pathologic role of the PD-1 pathway in most common lymphoid malignancies and we organize the clinical data from clinical trials of PD-1 pathway inhibitors. Several anti-PD-1 regimens have shown encouraging therapeutic effects in patients with relapsed or refractory Hodgkin lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. Additional progress is needed to foster an improved understanding of the role of anti-PD-1 therapy in reconstituting antitumor immunity in patients with lymphoid malignancies. Upcoming trials will explore the clinical efficiency of combining PD-1 pathway inhibitors and various agents with diverse mechanisms of action and create more therapeutic possibilities for afflicted patients.
Assuntos
Antígeno B7-H1/fisiologia , Linfoma/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/fisiologia , Receptor de Morte Celular Programada 1/fisiologia , Transdução de Sinais/fisiologia , Animais , Humanos , Linfoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/químicaRESUMO
BACKGROUND: The natural history of asthma includes in some patients periods of disease remission, but the underlying mechanisms are unknown. OBJECTIVES: We explored whether type 1 myeloid dendritic cell (mDC) dysfunction could be involved in the persistence of asthma, studying the controlled setting of occupational asthma after allergen avoidance. METHODS: We recruited 32 patients with occupational asthma to flour or latex ascertained by specific inhalation challenge and who were no longer exposed to the causal allergen. Leukapheresis was performed in each patient to isolate and characterise blood type 1 mDCs, and their functionality was studied in coculture with allogeneic CD4(+) T cells from controls. RESULTS: At follow-up, 11/32 patients (34%) were characterised by the absence of symptoms and non-specific bronchial hyper-responsiveness to histamine and were considered to be cured. When compared with cured patients, mDCs from patients with persistent disease increased the production of interleukin (IL) 5 and IL-13 by CD4(+) T cells, and upregulated programmed death ligand 2 (PD-L2) upon allergen pulsing. In addition, IL-5 and IL-13 responses could be reversed by exogenous IL-12, as well as by PD-L2 blockade. CONCLUSIONS: This study indicates that pro-Th2 features of mDCs correlate with disease activity in asthma after cessation of exposure to the causal allergen. The findings also highlight that the Th2 programming by dendritic cells is flexible and partly mediated by PD-L2.
Assuntos
Asma Ocupacional/etiologia , Linfócitos T CD4-Positivos/fisiologia , Células Dendríticas/fisiologia , Células Mieloides/fisiologia , Alérgenos , Asma Ocupacional/metabolismo , Asma Ocupacional/patologia , Farinha , Humanos , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Látex , Proteína 2 Ligante de Morte Celular Programada 1/fisiologiaRESUMO
Memory B cells (MBCs) are long-lived sources of rapid, isotype-switched secondary antibody-forming cell (AFC) responses. Whether MBCs homogeneously retain the ability to self-renew and terminally differentiate or if these functions are compartmentalized into MBC subsets has remained unclear. It has been suggested that antibody isotype controls MBC differentiation upon restimulation. Here we demonstrate that subcategorizing MBCs on the basis of their expression of CD80 and PD-L2, independently of isotype, identified MBC subsets with distinct functions upon rechallenge. CD80(+)PD-L2(+) MBCs differentiated rapidly into AFCs but did not generate germinal centers (GCs); conversely, CD80(-)PD-L2(-) MBCs generated few early AFCs but robustly seeded GCs. The gene-expression patterns of the subsets supported both the identity and function of these distinct MBC types. Hence, the differentiation and regeneration of MBCs are compartmentalized.