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1.
Medicine (Baltimore) ; 98(41): e17348, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593084

RESUMO

Immune checkpoint inhibitors (ICIs) like cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and programmed death cell protein 1 (anti-PD1) have revolutionized cancer treatment. As ICI use becomes widespread, more immune-related adverse events (irAE's) are being reported. Our aim was to investigate the frequency and nature of new irAE's as well as report the frequency of flare-ups of pre-existing autoimmune conditions occurring after ICI therapy.We performed a retrospective chart review of all patients treated for cancer with anti-PD1 or anti-CTLA4 or combination therapy at our tertiary care center from January 2014 to April 2016. Demographic data, cancer type and stage, irAE's (new immune disorders and disease flares of pre-existing autoimmune disorders on ICI therapy), and drug treatment information were extracted.We identified 220 patients treated with ICI therapy during the study period out of which 27% (60/220) developed irAE's. 11% in anti-CTLA4 group and 16% among anti-PD1 treated patients developed irAE's. IrAE's resulted in discontinuation of cancer therapy in 28% of those who developed irAE's. 21.4% had a flare of their autoimmune disease but only 1 required discontinuation of immunotherapy.IrAE's are an important emerging clinical disease entity for specialists to be aware of. Our study shows that ICI's can be safely used in patients with pre-existing autoimmune conditions with close monitoring. However, there is still a large unmet need to have a better understanding of how to systematically evaluate and manage patients with irAE's as well as for identifying the predictors of irAE's.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doenças do Sistema Imunitário/induzido quimicamente , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos
2.
Nature ; 574(7776): 122-126, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554970

RESUMO

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.


Assuntos
Doenças do Sistema Imunitário/imunologia , Isotipos de Imunoglobulinas/análise , Isotipos de Imunoglobulinas/imunologia , Receptores de Antígenos de Linfócitos B/análise , Receptores de Antígenos de Linfócitos B/imunologia , Adulto , Idoso , Células Clonais/citologia , Células Clonais/imunologia , Humanos , Imunoglobulina A/análise , Imunoglobulina A/imunologia , Switching de Imunoglobulina/imunologia , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Pessoa de Meia-Idade , Adulto Jovem
3.
Vet Immunol Immunopathol ; 214: 109902, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31378221

RESUMO

Autoantibodies against cytokines have been associated with immunodeficiency, susceptibility to infectious diseases, autoimmunity and inflammation in humans, but have not yet been investigated in the Veterinary field so far. The aim of the current study was to determine the presence of anti-cytokine autoantibodies in canines suffering from various conditions including recurrent infections, autoimmune diseases and cancer in comparison to healthy controls. This is the first report of the presence of autoantibodies against cytokines in dogs. A total of 101 serum samples (51 patients and 50 clinically healthy dogs) from the state of Mexico and surroundings were analysed using a multiplex bead-based flow cytometry assay. Results show significant levels of various anti-cytokine autoantibodies in diseased dogs but not in healthy controls. In addition we show distinct associations of various disease types to the specificity of anti-cytokine autoantibodies and to response complexities. Apart from the direct functional/causal implication of anti-cytokine auto-antibodies on disease processes, this findings point to the possibility to use anti-cytokine response patterns as diagnostic tools.


Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/veterinária , Citocinas/imunologia , Doenças do Sistema Imunitário/veterinária , Animais , Doenças Autoimunes/imunologia , Cães , Feminino , Doenças do Sistema Imunitário/imunologia , Incidência , Masculino , México , Neoplasias/imunologia , Neoplasias/veterinária
5.
Lancet Psychiatry ; 6(7): 620-630, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31196793

RESUMO

Catatonia is a psychomotor disorder featuring stupor, posturing, and echophenomena. This Series paper examines the evidence for immune dysregulation in catatonia. Activation of the innate immune system is associated with mutism, withdrawal, and psychomotor retardation, which constitute the neurovegetative features of catatonia. Evidence is sparse and conflicting for acute-phase activation in catatonia, and whether this feature is secondary to immobility is unclear. Various viral, bacterial, and parasitic infections have been associated with catatonia, but it is primarily linked to CNS infections. The most common cause of autoimmune catatonia is N-methyl-D-aspartate receptor (NMDAR) encephalitis, which can account for the full spectrum of catatonic features. Autoimmunity appears to cause catatonia less by systemic inflammation than by the downstream effects of specific actions on extracellular antigens. The specific association with NMDAR encephalitis supports a hypothesis of glutamatergic hypofunction in catatonia.


Assuntos
Catatonia/complicações , Catatonia/imunologia , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/fisiopatologia , Catatonia/fisiopatologia , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Doenças do Sistema Imunitário/imunologia
6.
Hum Cell ; 32(3): 231-239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079327

RESUMO

Innate lymphoid cells (ILCs) are a recently described group of innate immune cells that mirror the characteristics of CD4+ T cell subsets. Based on their transcriptional factor and cytokine profile, ILCs family is divided into main subgroups-ILC1s, ILC2s, and ILC3s. Recently, one new subpopulation of ILCs with immunosuppressive characteristics has been described and named as regulatory ILCs. Various roles of ILCs have been confirmed including the role during the response to microbial signals, the role in inflammation and process of tissue repair. Function of ILCs is mediated through the cytokines production and direct cell-to-cell contact. This article summarizes in detail, the relationship between the ILCs and various immune-related disorders.


Assuntos
Doenças do Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Humanos , Tolerância Imunológica , Inflamação/imunologia
7.
Int J Mol Sci ; 20(9)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31052382

RESUMO

Dendritic cells (DCs) are the professional antigen-presenting cells that recognize and present antigens to naïve T cells to induce antigen-specific adaptive immunity. Among the T-cell subsets, T helper type 2 (Th2) cells produce the humoral immune responses required for protection against helminthic disease by activating B cells. DCs induce a Th2 immune response at a certain immune environment. Basophil, eosinophil, mast cells, and type 2 innate lymphoid cells also induce Th2 immunity. However, in the case of DCs, controversy remains regarding which subsets of DCs induce Th2 immunity, which genes in DCs are directly or indirectly involved in inducing Th2 immunity, and the detailed mechanisms underlying induction, regulation, or maintenance of the DC-mediated Th2 immunity against allergic environments and parasite infection. A recent study has shown that a genetic defect in DCs causes an enhanced Th2 immunity leading to severe atopic dermatitis. We summarize the Th2 immune-inducing DC subsets, the genetic and environmental factors involved in DC-mediated Th2 immunity, and current therapeutic approaches for Th2-mediated immune disorders. This review is to provide an improved understanding of DC-mediated Th2 immunity and Th1/Th2 immune balancing, leading to control over their adverse consequences.


Assuntos
Células Dendríticas/imunologia , Doenças do Sistema Imunitário/imunologia , Células Th2/imunologia , Animais , Humanos , Doenças do Sistema Imunitário/terapia , Imunoterapia/métodos
8.
Genes Immun ; 20(5): 415-425, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31000797

RESUMO

Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis cause significant morbidity and are a considerable burden for the patients in terms of pain, impaired function, and diminished quality of life, as well as for society, because of the associated high health-care costs and loss of productivity. Our limited understanding of the pathogenic mechanisms involved in these diseases currently hinders early diagnosis and the development of more specific and effective therapies. The past years have been marked by considerable progress in our insight of the genetic basis of many diseases. In particular, genome-wide association studies (GWAS) performed with thousands of patients have provided detailed information about the genetic variants associated with a large number of chronic inflammatory diseases. These studies have brought to the forefront many genes linked to signaling pathways that were not previously known to be involved in pathogenesis, pointing to new directions in the study of disease mechanisms. GWAS also provided fundamental evidence for a key role of the immune system in the pathogenesis of these diseases, because many of the identified loci map to genes involved in different immune processes. However, the mechanisms by which disease-associated genetic variants act on disease development and the targeted cell populations remain poorly understood. The challenge of the post-GWAS era is to understand how these variants affect pathogenesis, to allow translation of genetic data into better diagnostics and innovative treatment strategies. Here, we review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients.


Assuntos
Predisposição Genética para Doença , Doenças do Sistema Imunitário/genética , Interleucina-17/imunologia , Interleucina-23/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Interleucina-17/genética , Interleucina-23/genética
10.
Vnitr Lek ; 65(2): 81-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909697

RESUMO

IL-1 family represent a group of structurally related cytokines with prevailing pro-inflammatory (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β a IL-37γ) or anti-inflammatory (IL-1Ra, IL-36Ra, IL-38, IL-37) effects. They are involved not only in defense mechanisms and physiological modulation of homeostatic processes, but also in the imunopathogenesis of many diseases including rheumatoid arthritis, inflammatory bowel disease, autoimmune and auto-inflammatory diseases. Recently, advances in biologic therapy enabled blocking of IL-1α, IL-1β, IL-18, and IL-33 with new monoclonal antibodies, soluble receptors, or recombinant binding proteins.


Assuntos
Artrite Reumatoide , Citocinas , Doenças do Sistema Imunitário , Interleucina-1 , Artrite Reumatoide/imunologia , Doença Crônica , Humanos , Doenças do Sistema Imunitário/imunologia , Fatores Imunológicos , Interleucinas
11.
Vnitr Lek ; 65(2): 98-107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909699

RESUMO

Each individual is colonized by broad spectrum of microbes. Recent surge of interest in microbiota across all fields of medicine was motivated by an increasing body of knowledge on how commensals influence human health. This is most notable in the gut, where most microbes reside, but microbes colonizing other niches, such as oral cavity or skin, may influence health as well. Microbiota fundamentally influences the immune system development and its perturbation, i.e. dysbiosis, is associated with many inflammatory, autoimmune and neoplastic diseases. Microbiota forms a symbiotic relationship with the host - maintaining balanced and efficient immune response and protects from colonization by pathogens. Modern medicine may benefit greatly by adopting these ideas for therapeutic or prophylactic purposes. These may include manipulation with microbiota by diet, changes in lifestyle or directly by probiotics or fecal microbiota transfer.


Assuntos
Microbioma Gastrointestinal , Doenças do Sistema Imunitário , Microbiota , Probióticos , Disbiose , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/microbiologia
12.
BMC Med ; 17(1): 60, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30862316

RESUMO

BACKGROUND: There are over 200 million reported cases of malaria each year, and most children living in endemic areas will experience multiple episodes of clinical disease before puberty. We set out to understand how frequent clinical malaria, which elicits a strong inflammatory response, affects the immune system and whether these modifications are observable in the absence of detectable parasitaemia. METHODS: We used a multi-dimensional approach comprising whole blood transcriptomic, cellular and plasma cytokine analyses on a cohort of children living with endemic malaria, but uninfected at sampling, who had been under active surveillance for malaria for 8 years. Children were categorised into two groups depending on the cumulative number of episodes experienced: high (≥ 8) or low (< 5). RESULTS: We observe that multiple episodes of malaria are associated with modification of the immune system. Children who had experienced a large number of episodes demonstrated upregulation of interferon-inducible genes, a clear increase in circulating levels of the immunoregulatory cytokine IL-10 and enhanced activation of neutrophils, B cells and CD8+ T cells. CONCLUSION: Transcriptomic analysis together with cytokine and immune cell profiling of peripheral blood can robustly detect immune differences between children with different numbers of prior malaria episodes. Multiple episodes of malaria are associated with modification of the immune system in children. Such immune modifications may have implications for the initiation of subsequent immune responses and the induction of vaccine-mediated protection.


Assuntos
Doenças do Sistema Imunitário/imunologia , Malária/imunologia , Criança , Pré-Escolar , Humanos
13.
Expert Opin Drug Saf ; 18(3): 219-229, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30704314

RESUMO

INTRODUCTION: TNF-α inhibitors can be administered either as monotherapy or in combination with other anti-inflammatory drugs or DMARDs in the treatment of chronic immune-mediated diseases. AREAS COVERED: Patients receiving TNF-α inhibitors are at high risk of infections. An update is made on the risk of infection in patients receiving TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events. EXPERT OPINION: Infliximab than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis infection and the overall risk of opportunistic infections should be considered before beginning a course of TNF-α inhibitors. A careful medical history, Mantoux test/quantiferon-TB Gold In-tube Test and chest-X-ray should always be performed before starting TNF-α inhibitors. Particular attention should be paid to risk factors for Pneumocystis jirovecii infection. Hepatitis B and C virological follow-up should be considered during TNF-α inhibitors treatment. Finally, appropriate vaccinations for influenza, S. pneumoniae, and HBV should be administered to decrease the risk of infection, and patients who are at high risk of herpes zoster reactivation would benefit from a second vaccination in adulthood.


Assuntos
Doenças do Sistema Imunitário/tratamento farmacológico , Infecção/etiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Humanos , Doenças do Sistema Imunitário/imunologia , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Infecção/epidemiologia , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/etiologia , Fatores de Risco
14.
Allergol. immunopatol ; 47(1): 90-104, ene.-feb. 2019.
Artigo em Inglês | IBECS | ID: ibc-180778

RESUMO

T helper 9 (TH9) cells are considered as newly classified helper T cells that have an important role in the regulation of immune responses. Since these cells preferentially produce IL-9, these cells are termed TH9 cells. Recently, the role of TH9 and its signature cytokine (IL-9) has been investigated in a wide range of diseases, including autoimmunity, allergy, infections, cancer and immunodeficiency. Herein, we review the most recent data concerning TH9 cells and IL-9 as well as their roles in disease. These insights suggest that TH9 cells are a future target for therapeutic intervention


No disponible


Assuntos
Humanos , Animais , Doenças do Sistema Imunitário/imunologia , Imunoterapia/métodos , Interleucina-9/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Autoimunidade
15.
Ann Hematol ; 98(5): 1177-1184, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30610278

RESUMO

Immunoparesis is defined as a reduction in the levels of one, two, or three uninvolved immunoglobulins. However, there are very limited data on the incidence and prognostic significance of immunoparesis recovery 1 year after autologous stem cell transplantation (ASCT) in MM. We reviewed medical records of de novo MM patients who received ASCT at Beijing Chao Yang hospital. One hundred eight MM patients were included in the study. Conventional chemotherapy was administered as induction regimen in 16 patients (14.8%), whereas novel agents were used in 92 patients (85.2%). Most patients had immunoparesis at diagnosis (89.1%) and at the moment of ASCT as well (75%). After a median follow-up of 49 months, in the group with immunoglobulin recovery 1 year after ASCT, there was a trend towards longer progression-free survival (PFS) than in the group with immunoparesis (P = 0.054). And overall survival (OS) was significantly longer in patients with immunoparesis recovery (P = 0.004). In multivariate analysis, immunoparesis recovery 1 year after ASCT was independently associated with improved OS (P = 0.016). In conclusion, lack of immunoparesis recovery 1 year after ASCT in MM patients is associated with significantly shorter OS and this group of patients needs new treatment strategy to improve the prognosis.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doenças do Sistema Imunitário , Adulto , Idoso , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/mortalidade , Doenças do Sistema Imunitário/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Taxa de Sobrevida
16.
Toxicol Lett ; 304: 30-38, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30605750

RESUMO

Clinical study showed that smoking during pregnancy deceased the thymus size in newborns. However, the long-term effect remains unclear. This study was aimed to observe the effects of prenatal nicotine exposure (PNE) on the development of thymus and the T-lymphocyte subpopulation in mice offspring from the neonatal to adulthood. Both the thymus weight and cytometry data indicated that PNE caused persistent thymic hypoplasia in male offspring from neonatal to adult period and transient changes in female offspring from neonatal to prepuberal period. Flow cytometry analysis disclosed a permanent decreased proportion and number of mature CD4 single-positive (SP) T cells in thymus of both sex. In addition, the PNE male offspring showed a more serious thymus atrophy in the ovalbumin (OVA)-sensitized model. Moreover, increased autophagic vacuole and elevated mRNA expression of Beclin 1 were noted in PNE fetal thymus. In conclusion, PNE offspring showed thymus atrophy and CD 4 SP T cell reduction at different life stages. Mechanically, PNE induced excessive autophagy in fetal thymocytes might be involved in these changes. All the results provided evidence for elucidating the PNE-induced programmed immune diseases.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Doenças do Sistema Imunitário/induzido quimicamente , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Timócitos/efeitos dos fármacos , Timo/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Feminino , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/patologia , Masculino , Exposição Materna , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fenótipo , Gravidez , Timócitos/imunologia , Timócitos/metabolismo , Timócitos/patologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
17.
Curr Opin Allergy Clin Immunol ; 19(1): 1-6, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30543547

RESUMO

PURPOSE OF REVIEW: Microbiome refers to the genetic potential of resident microorganisms that inhabit a given niche. The exact role of the microbiome and its relation to chronic disease processes remains largely unknown, although various associations have been observed. We reviewed current literature investigating the microbiome of the upper airway by subsite (nasal cavity, sinus cavities, nasopharynx, and larynx) and its relation to chronic inflammatory disease processes. RECENT FINDINGS: The disruption of indigenous microbiota at a specific subsite may lead to pathogen overgrowth and increased susceptibility to infection. This has previously been demonstrated in the gastrointestinal tract and lower airways. The role of the microbiome and its relation to pathogenesis of disease in the upper airway, however, is less clearly understood. The present review discusses the recent studies that appear to link dysbiosis to upper airway chronic inflammatory diseases. SUMMARY: Despite mounting research, the role of microbiota in the upper airway remains poorly understood. Based on review of the current literature comparing healthy versus diseased patients with site-specific inflammatory conditions, a complex consortium of microbial communities inhabits the upper airway. Fluctuations in the baseline microbiome may contribute to disease pathogenesis, and improved understanding of the dynamics between shifting microbiota may be critical to guiding future medical therapy.


Assuntos
Disbiose/microbiologia , Doenças do Sistema Imunitário/microbiologia , Inflamação/imunologia , Microbiota/fisiologia , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Animais , Terapia Biológica , Suscetibilidade a Doenças , Disbiose/imunologia , Homeostase , Humanos , Doenças do Sistema Imunitário/imunologia , Inflamação/microbiologia
18.
Orv Hetil ; 159(49): 2079-2086, 2018 Dec.
Artigo em Húngaro | MEDLINE | ID: mdl-30525885

RESUMO

Characteristic lesions of the oral cavity in primary immunodeficiencies are commonly found in the form of periodontal disease, tooth decay and disorders of the oral mucosa. Humoral immunodeficiencies may cause tooth decay, while severe forms of plaque-induced periodontal disease are common in phagocytic deficiencies. The structural abnormalities of the teeth can occur in immunodeficiencies associated with apoptosis defect. Oral squamous cell carcinoma is a possible complication of immunodeficiencies associated with DNA repair defects. Orv Hetil. 2018; 159(49): 2079-2086.


Assuntos
Síndromes de Imunodeficiência/imunologia , Doenças Periodontais/imunologia , Humanos , Doenças do Sistema Imunitário/imunologia , Síndromes de Imunodeficiência/complicações , Doenças Periodontais/complicações
19.
PLoS One ; 13(12): e0209509, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30592762

RESUMO

Modulating the complement system is a promising strategy in drug discovery for disorders with uncontrolled complement activation. Although some of these disorders can be effectively treated with an antibody that inhibits complement C5, the high plasma concentration of C5 requires a huge dosage and frequent intravenous administration. Moreover, a conventional anti-C5 antibody can cause C5 to accumulate in plasma by reducing C5 clearance when C5 forms an immune complex (IC) with the antibody, which can be salvaged from endosomal vesicles by neonatal Fc receptor (FcRn)-mediated recycling. In order to neutralize the increased C5, an even higher dosage of the antibody would be required. This antigen accumulation can be suppressed by giving the antibody a pH-dependent C5-binding property so that C5 is released from the antibody in the acidic endosome and then trafficked to the lysosome for degradation, while the C5-free antibody returns back to plasma. We recently demonstrated that a pH-dependent C5-binding antibody, SKY59, exhibited long-lasting neutralization of C5 in cynomolgus monkeys, showing potential for subcutaneous delivery or less frequent administration. Here we report the details of the antibody engineering involved in generating SKY59, from humanizing a rabbit antibody to improving the C5-binding property. Moreover, because the pH-dependent C5-binding antibodies that we first generated still accumulated C5, we hypothesized that the surface charges of the ICs partially contributed to a slow uptake rate of the C5-antibody ICs. This idea motivated us to engineer the surface charges of the antibody. Our surface-charge engineered antibody consequently exhibited a high capacity to sweep C5 and suppressed the C5 accumulation in vivo by accelerating the cycle of sweeping: uptake of ICs into cells, release of C5 from the antibody in endosomes, and salvage of the antigen-free antibody. Thus, our engineered anti-C5 antibody, SKY59, is expected to provide significant benefits for patients with complement-mediated disorders.


Assuntos
Anticorpos Monoclonais/genética , Ativação do Complemento/efeitos dos fármacos , Complemento C5/antagonistas & inibidores , Engenharia de Proteínas/métodos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Afinidade de Anticorpos , Ativação do Complemento/imunologia , Complemento C5/imunologia , Complemento C5/isolamento & purificação , Simulação por Computador , Descoberta de Drogas/métodos , Endossomos/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Concentração de Íons de Hidrogênio , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Macaca fascicularis , Camundongos , Camundongos Transgênicos , Mutagênese , Receptores Fc/genética , Receptores Fc/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Fatores de Tempo
20.
Biol Pharm Bull ; 41(8): 1158-1163, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30068864

RESUMO

In lymphoid and myeloid cells, membrane hyperpolarization by the opening of K+ channels increases the activity of Ca2+ release-activated Ca2+ (CRAC) channels and transient receptor potential (TRP) Ca2+ channels. The intermediate-conductance Ca2+-activated K+ channel KCa3.1 plays an important role in cell proliferation, differentiation, migration, and cytokine production in innate and adaptive immune systems. KCa3.1 is therefore an attractive therapeutic target for allergic, inflammatory, and autoimmune disorders. In the past several years, studies have provided new insights into 1) KCa3.1 pharmacology and its auxiliary regulators; 2) post-transcriptional and proteasomal regulation of KCa3.1; 3) KCa3.1 as a regulator of immune cell migration, cytokine production, and phenotypic polarization; 4) the role of KCa3.1 in the phosphorylation and nuclear translocation of Smad2/3; and 5) KCa3.1 as a therapeutic target for cancer immunotherapy. In this review, we have assembled a comprehensive overview of current research on the physiological and pathophysiological significance of KCa3.1 in the immune system.


Assuntos
Doenças do Sistema Imunitário/imunologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/imunologia , Animais , Movimento Celular , Citocinas/imunologia , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Fenótipo , Fosforilação , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo
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