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1.
Nat Med ; 25(9): 1402-1407, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501610

RESUMO

Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)1,2, but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation3,4. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4+ T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.


Assuntos
Anticorpos Neutralizantes/administração & dosagem , Epitopos de Linfócito T/imunologia , Esclerose Múltipla/tratamento farmacológico , Natalizumab/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Neutralizantes/química , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Linfócitos B/efeitos dos fármacos , Humanos , Imunoglobulina G/química , Imunoglobulina G/imunologia , Integrina alfa4/antagonistas & inibidores , Integrina alfa4/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Conformação Proteica/efeitos dos fármacos , Linfócitos T/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
2.
Clin Exp Rheumatol ; 37 Suppl 118(3): 217-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464681

RESUMO

Despite the well-established role of B cells in the pathogenesis of primary Sjögren's syndrome (pSS), the beneficial role of B-cell depletion therapy with rituximab remains elusive in this condition, contrary to other autoimmune diseases. Although early, small-scale studies showed promising results, two recent large randomised controlled trials did not meet their primary end-points. It is evident from most trials that rituximab has a positive impact on B-cell numbers and activity, both in the peripheral blood and in salivary glands, but clinical outcomes vary among studies. We review here the evidence to date of B-cell depletion in pSS, analysing the underlying causes for the discrepancies in different studies and their limitations. We also discuss the potential use of peripheral and salivary gland biomarkers for patient stratification and targeted patient selection. Overall, rituximab remains a plausible treatment for pSS provided future studies address the shortfalls that emerged from our current knowledge of the use of B-cell depletion in this condition.


Assuntos
Linfócitos B , Rituximab/uso terapêutico , Síndrome de Sjogren , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Humanos , Depleção Linfocítica , Glândulas Salivares , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
3.
Carbohydr Polym ; 222: 114962, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31320077

RESUMO

The relevance of microalgae biotechnology for producing high-value compounds with biomedical application, such as polysaccharides, has been increasing. Despite this, the knowledge about the composition and structure of microalgae polysaccharides is still scarce. In this work, water-soluble polysaccharides from Nannochloropsis oculata were extracted, fractionated, structurally analysed, and subsequently tested in terms of immunostimulatory activity. A combination of sugar and methylation analysis with interaction data of carbohydrate-binding proteins using carbohydrate microarrays disclosed the complex structural features of the different polysaccharides. These analyses showed that the water-soluble polysaccharides fractions from N. oculata were rich in (ß1→3, ß1→4)-glucans, (α1→3)-, (α1→4)-mannans, and anionic sulphated heterorhamnans. The immunostimulatory assay highlighted that these fractions could also stimulate murine B-lymphocytes. Thus, the N. oculata water-soluble polysaccharides show potential to be further explored for immune-mediated biomedical applications.


Assuntos
Linfócitos B/efeitos dos fármacos , Microalgas/química , Polissacarídeos/imunologia , Estramenópilas/química , Animais , Desoxiaçúcares/análise , Glucanos/análise , Imunização , Mananas/análise , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos/química , Polissacarídeos/farmacologia
4.
J Food Sci ; 84(6): 1577-1585, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31120637

RESUMO

A mixture of multiple ingredients is often more effective than the individual ingredients. The functions of Lycium barbarum polysaccharide (LBP) glycoconjugate and grape seed procyanidins (GSP) are widely known. Here, we investigated the synergistic immune-enhancing activity of LBP and GSP. Atomic force microscopy results suggested that the mixture of LBP and GSP exhibited circular structure unlike LBP alone, and the addition of polyphenols may change the spatial conformation of the sugar chain. The changes in the structure were related to the synergistic effect of the two functional agents on immune recovery. In vitro, the proliferation rate of splenocytes was higher in LBP + GSP group (64.16%), rather than the sum of LBP group (13.01%) and GSP group (43.61%) individually used. This synergistical proliferation of splenocytes may be correlated to the increasing intracellular free calcium levels. Furthermore, the mixture significantly enhanced the immunity in vivo, as evident from the recovery of peripheral white blood cell counts in LBP + GSP group (18.535 × 109 /L) to normal group levels (18.115 × 109 /L) and higher B cell proliferation than normal group (P < 0.05). These results highlight the immune-enhancing activity of the combination of LBP and GSP associated with the structural changes, which may facilitate the development of functional foods with fewer resources but enhanced activities. PRACTICAL APPLICATION: The synergistic effects of LBP and GSP on immunomodulatory were better than the sum of the effects of the individual agents both in vitro and in vivo. Our results may provide a research-based support for the development of related functional products and an insight into the production of food resources with a fewer but more effective functional agents for better results.


Assuntos
Biflavonoides/administração & dosagem , Catequina/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Imunidade/efeitos dos fármacos , Lycium/química , Extratos Vegetais/administração & dosagem , Proantocianidinas/administração & dosagem , Vitis/química , Animais , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Biflavonoides/química , Catequina/química , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Feminino , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Proantocianidinas/química , Sementes/química
5.
Pharm Res ; 36(6): 82, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30989405

RESUMO

PURPOSE: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. METHODS: Twenty B cell non-Hodgkin's lymphoma patients who were treated with rituximab for the first time or after more than one year's abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. RESULTS: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. CONCLUSION: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.


Assuntos
Antineoplásicos/química , Linfócitos B/efeitos dos fármacos , Glicoproteínas/química , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/química , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Feminino , Glicoproteínas/administração & dosagem , Glicoproteínas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Plasma , Conformação Proteica , Rituximab/administração & dosagem , Rituximab/farmacocinética
6.
Eur J Med Chem ; 170: 112-125, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878826

RESUMO

A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identified with single-digit nanomolar IC50 values against PI3Kδ and submicromolar GI50 values against human malignant B-cell line SU-DHL-6. Furthermore, chiral resolution of the key amine intermediate of these two compounds was performed to achieve corresponding enantiomers. In subsequent biological evaluation, S-63 (IC50: 4.6 nM) and S-71 (IC50: below 0.32 nM) demonstrated comparable and superior PI3Kδ inhibitory activity, respectively, to that of idelalisib. Additionally, both S-63 (GI50: 33.2 nM) and S-71 (GI50: 15.9 nM) exerted enhanced anti-proliferative activity against the SU-DHL-6 cell line than that of idelalisib. Moreover, both S-63 and S-71 exhibited excellent PI3Kδ selectivity. In the further in vivo pharmacokinetic (PK) study, S-63 displayed a good plasma exposure and an acceptable oral bioavailability of 29.2%. By virtue of its biological performance, S-63 merits further development as a potential therapeutic agent for battling B-cell-mediated malignancies.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzotiadiazinas/química , Benzotiadiazinas/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/patologia , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Desenho de Drogas , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley
7.
Fitoterapia ; 134: 481-484, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30910737

RESUMO

Further chemical investigation of the South China Sea soft coral Lemnalia flava resulted in the isolation and characterization of two new cembranoids, namely, xishaflavalins G and H (1 and 2), along with three known related compounds (3-5). The structures of the new compounds were elucidated by detailed spectroscopic analysis and by the comparison of their spectroscopic data with those reported in the literature. The discovery of cembrane-type diterpenes from soft coral of the genus Lemnalia was reported for the first time. In addition, compound 5 exhibited moderate inhibitory effects on the ConA-induced T lymphocytes and/or lipopolysaccharide (LPS)-induced B lymphocytes proliferation.


Assuntos
Antozoários/química , Linfócitos B/efeitos dos fármacos , Diterpenos/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Células Cultivadas , China , Diterpenos/isolamento & purificação , Feminino , Camundongos Endogâmicos BALB C , Estrutura Molecular
8.
J Oncol Pharm Pract ; 25(6): 1467-1472, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30917739

RESUMO

Hairy cell leukemia is a rare indolent B-cell lymphoid malignancy. Durable remission can be obtained with purine analogues, but relapse is inevitable, and effective treatment options may be limited. Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin that has recently been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory hairy cell leukemia. Approval was based on a pivotal phase III study in this unique patient population. Rationale for use, clinical trial data, and current treatment recommendations are detailed. Common adverse effects are reviewed, and management strategies for select adverse effects are suggested. Implications for contemporary practitioners are also provided, as use of this novel agent is likely to increase as follow-up studies are reported.


Assuntos
Antineoplásicos/uso terapêutico , Toxinas Bacterianas/uso terapêutico , Exotoxinas/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/patologia , Toxinas Bacterianas/efeitos adversos , Toxinas Bacterianas/metabolismo , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Exotoxinas/efeitos adversos , Exotoxinas/metabolismo , Seguimentos , Humanos , Hipotensão/induzido quimicamente , Leucemia de Células Pilosas/metabolismo , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Resultado do Tratamento
9.
Food Funct ; 10(4): 2030-2039, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30907398

RESUMO

Resveratrol exists widely in plant species and has a variety of anti-oxidant, anti-inflammatory, and immunomodulatory properties. However, there have been few reports regarding its anti-food allergic activity. In this study, we demonstrated that resveratrol (isolated from Abies georgei) could decrease the release of ß-hexosaminidase and histamine in rat basophilic leukemia-2H3 cells. Resveratrol was not only found to suppress the development of diarrhea, up-regulate the rectal temperature of ovalbumin-allergic mice, and decrease the serum level of specific immunoglobulin E, mouse mast cell protease-1 and histamine, but also found to decrease the population of dendritic cells, B cells and mast cells of ovalbumin -allergic mice in the spleen or mesenteric lymph node. Furthermore, resveratrol inhibited the release of ß-hexosaminidase and histamine in bone marrow-derived cells and alleviated mast cell-mediated passive cutaneous anaphylaxis reactions. These findings indicated that resveratrol isolated from Abies georgei might have the potential to alleviate food hypersensitivity or allergic disease.


Assuntos
Abies/química , Antialérgicos/administração & dosagem , Hipersensibilidade Alimentar/tratamento farmacológico , Mastócitos/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Resveratrol/administração & dosagem , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Hipersensibilidade Alimentar/etiologia , Hipersensibilidade Alimentar/imunologia , Histamina/imunologia , Humanos , Imunoglobulina E/imunologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/efeitos adversos , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Peptídeo Hidrolases/imunologia , Ratos , beta-N-Acetil-Hexosaminidases/imunologia
10.
Biomed Pharmacother ; 114: 108804, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909146

RESUMO

B lymphocytes have been shown to contribute to autoimmune diseases via producing antibodies and proinflammatory cytokines. Depletion of B cells by blocking CD20 can inhibit these diseases. Here we examined whether an antibody against CD20, rituximab (RTX) (Rituxan@), used clinically in oncology could have similar anti-inflammatory effects in cardiac remodeling and heart failure (HF) in mice. Cardiac remodeling was established by pressure overload induced by transverse aortic constriction (TAC). Wild-type (WT) male C57BL/6 J mice were subjected to pressure overload by using transverse aortic constriction and then received RTX for 4 weeks. Administration of RTX markedly improves in vivo heart function, and suppressed heart chamber dilation, myocyte hypertrophy, fibrosis and oxidative stress in mice after TAC operation. RTX treatment also reversed established hypertrophic remodeling induced by TAC. Moreover, TAC-induced activation of multiple signaling pathways including calcineurin A, ERK1/2, STAT3, TGFß/Smad2/3 and IKKα/ß/NF-kB were remarkably attenuated in RTX-treated hearts compared with controls. These inhibitory effects of RTX were associated with inhibition of proinflammatory cytokine expression and Th2 cytokine-mediated IgG production from B cells. In conclusion, this study identifies that administration of RTX can inhibit pressure overload-induced cardiac remodeling and dysfunction in mice, and suggest that RTX may be a promising drug for treating hypertrophic disease.


Assuntos
Linfócitos B/efeitos dos fármacos , Coração/efeitos dos fármacos , Rituximab/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Hipertrofia/tratamento farmacológico , Hipertrofia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
11.
J Drugs Dermatol ; 18(3): 235-238, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30909326

RESUMO

Low-dose naltrexone (LDN) has been successfully studied as an immunomodulatory and anti-inflammatory therapy in a wide range of conditions including Crohn's disease, fibromyalgia, major depressive disorder, cancer, chronic regional pain syndrome, Charcot-Marie-Tooth, and multiple sclerosis.1-5 Recently, off label LDN has been shown to improve dermatologic conditions such as systemic sclerosis, Hailey-Hailey Disease, lichen planopilaris, and guttate psoriasis.6-9 In this article, we examine the existing evidence for use of LDN in skin disease and discuss its potential application in the treatment of atopic dermatitis (AD). J Drugs Dermatol. 2019;18(3):235-238.


Assuntos
Dermatite Atópica/tratamento farmacológico , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Uso Off-Label , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ensaios Clínicos como Assunto , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Relação Dose-Resposta a Droga , Humanos , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos , Receptores Opioides/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
12.
J Neuroimmunol ; 330: 81-86, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30851542

RESUMO

The aim of this study was to observe the treatment effect and investigate the possible mechanism of reduced dosage (600 mg) rituximab treatment on anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. The median modified Rankin Scale of ten enrolled patients decreased from 4 (range 2-4) before rituximab infusion to 0 (range 0-2) after a mean follow-up time of 24.3 ±â€¯8.7 months. One patient relapsed 9 months after treatment. No severe adverse event was observed. The proportion of total B cells in lymphocytes was depleted from 13.4 ±â€¯6.7% to 0.6 ±â€¯0.8% one day after treatment. B cells started to regeneration at 3 months and reached 9.4 ±â€¯3.7% at 12 months after treatment. At this time point, proportion of regulatory B cells (Breg) in reconstituted B cells was significantly higher than that before treatment (15.3 ±â€¯12.1% vs. 0.5 ±â€¯0.6%, p = 0.006), while proportion of memory B cells (Bmem) was significantly lower than baseline level (8.0 ±â€¯4.5% vs. 30.2 ±â€¯12.6%, p < 0.001). Our results supported that reduced dosage rituximab was effective and safe in treating anti-NMDAR encephalitis. B cell depletion and rebalance of Breg and Bmem might be involved in the treatment mechanism of this therapy.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Grupo com Ancestrais do Continente Asiático , Fatores Imunológicos/administração & dosagem , Rituximab/administração & dosagem , Adolescente , Adulto , Encefalite Antirreceptor de N-Metil-D-Aspartato/sangue , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
13.
Arch Pharm Res ; 42(2): 171-181, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30706214

RESUMO

BTK is a key component of B-cell receptor signaling and functions as an important regulator of cell proliferation and survival in B-cell malignancies. The first-in-class BTK inhibitor ibrutinib is a small molecule drug that binds covalently to BTK and has been proved to be an effective treatment for various B-cell malignancies. However, it has off-target activities on non-BTK kinases that are related to side effects or might be translated into clinical limitations, with resistance to ibrutinib also reported. Much progress has been made in the development of more selective and second-generation BTK inhibitors. A recent shift in the mechanisms of action of BTK inhibitors is noteworthy, and novel inhibitors acting through noncovalent BTK inhibition are now being developed. This review describes key characteristics of ibrutinib, including current issues of its clinical use, and summarizes preclinical properties and clinical developments of second-generation BTK inhibitors for the treatment of B-cell malignancies. A review of novel noncovalent BTK inhibitors are also included.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linfócitos B/enzimologia , Desenvolvimento de Medicamentos/métodos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Desenvolvimento de Medicamentos/tendências , Humanos , Linfoma de Células B/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento
14.
Leukemia ; 33(3): 576-587, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30700840

RESUMO

Targeting of B cell receptor associated kinases (BAKs), such as Bruton's tyrosine kinase (BTK) or phosphoinositol-3-kinase (PI3K) delta, by specific inhibitors has revolutionized the therapy of B lymphoid malignancies. BAKs are critical signaling transducers of BCR signaling and seem relevant in B cell lymphoma pathogenesis. The functional relevance of BTK for lymphoid malignancies is strongly supported by the observation that resistance to therapy in CLL patients treated with BTK inhibitors such as ibrutinib is often associated with mutations in genes coding for BTK or Phospholipase-C gamma (PLCÉ£). In some contrast, next generation sequencing data show that BAKs are mutated at very low frequency in treatment-naïve B cell lymphomas. Therefore, it remains debatable whether BAKs are essential drivers for lymphoma development. In addition, results obtained by targeted deletion of BAKs such as Lyn and Btk in murine CLL models suggest that BAKs may be essential to shape the dialogue between malignant B cells and the tumor microenvironment (TME). Since BAKs are expressed in multiple cell types, BAK inhibitors may disrupt the lymphoma supportive microenvironment. This concept also explains the typical response to BAK inhibitor treatment, characterized by a long-lasting increase of peripheral blood lymphoid cells, due to a redistribution from the lymphoid homing compartments. In addition, BAK inhibitors have shown some efficacy in solid tumors, probably through mediator cells in the TME. This review summarizes and validates the evidence for BAK inhibitors being part of a class of agents that modulate the (hematopoietic) microenvironment of cancers.


Assuntos
Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Antígenos de Linfócitos B/metabolismo , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
15.
Int Immunopharmacol ; 70: 80-87, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30785094

RESUMO

Alpha-MMC is a type I ribosome-inactivating protein purified from bitter gourd that has strong anti-tumour and antiviral activity. Alpha-MMC also has immunosuppressive effects, but the mechanism of these immunosuppressive effects remains unclear. It is reported that the binding of α-MMC to its specific cell membrane LRP1 receptor is key to its biological effects. In this study, we investigated the effect of α-MMC on cytotoxicity and cytokine release regulation in three immune cells, human monocyte THP-1 cells, B-lymphocyte WIL2 cells and T-lymphocyte H9 cells, and explored the correlation between this effect and LRP1 receptor distribution on these three cell types. We demonstrate that α-MMC has a significant effect of apoptosis induction and cytokine release in THP-1 cells but has no effect on WIL2-S and H9 cells. Specifically, at a non-cytotoxic dose (80 µg/ml), α-MMC regulates THP-1 cells by inhibiting IL-1ß, IL-2, IL-8, IL-9, IL-12, MIP-1α/ß, MCP-1 and TNF-α expression and enhancing IL-1ra and RANTES expression, resulting in the inhibition of cellular immune function. Subsequent experiments showed that the cytokine expression regulated by α-MMC can be blocked by silencing the LRP1 receptor of α-MMC. Further research indicated that phosphorylation of 9 signalling proteins of the MAPK pathway was significantly regulated by α-MMC and was blocked by LRP1 silencing. We conclude that the regulation of cytokine expression induced by α-MMC in monocyte THP-1 cells is mediated by the LRP1 receptor, likely via the MAPK signalling pathway. Our results suggest that the inhibition effect on monocytes/macrophages mediates the immunosuppressive function of α-MMC. Due to the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes/macrophages, α-MMC may be used for killing Tumour-Associated Macrophages (M2 subtypes) or inhibiting their cytokine release in the tumour microenvironment.


Assuntos
Linfócitos B/efeitos dos fármacos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Monócitos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Apoptose , Linfócitos B/imunologia , Quimiocina CCL5/metabolismo , Citocinas/metabolismo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Sistema de Sinalização das MAP Quinases , Monócitos/imunologia , Fosforilação , Proteínas Inativadoras de Ribossomos , Linfócitos T/imunologia , Células THP-1 , Microambiente Tumoral
16.
J Enzyme Inhib Med Chem ; 34(1): 692-702, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30777474

RESUMO

Matriptase is ectopically expressed in neoplastic B-cells, in which matriptase activity is enhanced by negligible expression of its endogenous inhibitor, hepatocyte growth factor activator inhibitor (HAI)-1. HAI-1, however, is also involved in matriptase synthesis and intracellular trafficking. The lack of HAI-1 indicates that other related inhibitor, such as HAI-2, might be expressed. Here, we show that HAI-2 is commonly co-expressed in matriptase-expressing neoplastic B-cells. The level of active matriptase shed after induction of matriptase zymogen activation in 7 different neoplastic B-cells was next determined and characterised. Our data reveal that active matriptase can only be generated and shed by those cells able to activate matriptase and in a rough correlation with the levels of matriptase protein. While HAI-2 can potently inhibit matriptase, the levels of active matriptase are not proportionally suppressed in those cells with high HAI-2. Our survey suggests that matriptase proteolysis might aberrantly remain high in neoplastic B-cells regardless of the levels of HAI-2.


Assuntos
Linfócitos B/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glicoproteínas de Membrana/biossíntese , Proteólise/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Humanos , Glicoproteínas de Membrana/metabolismo , Serina Endopeptidases/biossíntese
17.
Exp Clin Transplant ; 17(Suppl 1): 105-109, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777532

RESUMO

OBJECTIVES: Rituximab treatment strategies vary in ABOincompatible pediatric kidney transplant recipients. Here, we present the efficacy of 2 doses of rituximab and subsequent outcomes in ABO-incompatible pediatric kidney transplant patients. MATERIALS AND METHODS: Our study of ABO-incompatible pediatric kidney transplant recipients included 21 who were pretreated with desensitization that included 2 doses of 100 mg rituximab (rituximab group) at 10 and 1 day pretransplant and 14 who received splenectomy without rituximab (splenectomy group). Both groups received immunosuppression. Basiliximab was administered during transplant and 4 days posttransplant. Double-filtration plasmapheresis and/or plasma exchange procedures were performed pretransplant in those with higher antidonor antibody titers. CD19-positive and CD20-positive B cells were measured sequentially in the rituximab group. Maximum titers of antidonor antibody pre- and posttransplant, patient and graft survival, biopsy-proven rejection, and complications/infections were compared between groups. RESULTS: In the rituximab group, CD19- and CD20-positive B cells were depleted on transplant, persistently depleted at 3 months, and under 5% until 1 year posttransplant. Maximum titers of antidonor antibodies decreased significantly posttranplant in the rituximab (P < .001) but not in the splenectomy group (P = .174), with maximum titers posttransplant significantly lower than shown in the splenectomy group (P < .001). No rituximab patients had clinical rejection, but 5 splenectomy group patients had clinical T-cell-mediated rejection, with 2 also having antibody-mediated rejection. Six in the rituximab group had cytomegalovirus viremia but no cytomegalovirus disease; however, 5 splenectomy group recipients had cytomegalovirus disease and viremia. In the rituximab group, 3 had late-onset neutropenia. One child died of hypertrophic cardio myopathy with a functioning graft; all others survived with no failed grafts. All splenectomy group children survived, although 2 had deteriorated graft function. CONCLUSIONS: Two doses of rituximab were effective in long-term B-cell depletion to suppress antidonor antibodies. The possibility of late-onset neutropenia must be considered.


Assuntos
Sistema do Grupo Sanguíneo ABO/imunologia , Linfócitos B/efeitos dos fármacos , Incompatibilidade de Grupos Sanguíneos/imunologia , Rejeição de Enxerto/prevenção & controle , Histocompatibilidade , Imunossupressores/administração & dosagem , Isoanticorpos/imunologia , Transplante de Rim/métodos , Doadores Vivos , Rituximab/administração & dosagem , Fatores Etários , Linfócitos B/imunologia , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Masculino , Plasmaferese , Fatores de Risco , Rituximab/efeitos adversos , Esplenectomia , Fatores de Tempo , Resultado do Tratamento
18.
Nat Immunol ; 20(3): 362-372, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30742080

RESUMO

The present vaccine against influenza virus has the inevitable risk of antigenic discordance between the vaccine and the circulating strains, which diminishes vaccine efficacy. This necessitates new approaches that provide broader protection against influenza. Here we designed a vaccine using the hypervariable receptor-binding domain (RBD) of viral hemagglutinin displayed on a nanoparticle (np) able to elicit antibody responses that neutralize H1N1 influenza viruses spanning over 90 years. Co-display of RBDs from multiple strains across time, so that the adjacent RBDs are heterotypic, provides an avidity advantage to cross-reactive B cells. Immunization with the mosaic RBD-np elicited broader antibody responses than those induced by an admixture of nanoparticles encompassing the same set of RBDs as separate homotypic arrays. Furthermore, we identified a broadly neutralizing monoclonal antibody in a mouse immunized with mosaic RBD-np. The mosaic antigen array signifies a unique approach that subverts monotypic immunodominance and allows otherwise subdominant cross-reactive B cell responses to emerge.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Nanopartículas/química , Infecções por Orthomyxoviridae/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/virologia , Reações Cruzadas/efeitos dos fármacos , Reações Cruzadas/imunologia , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Humanos , Imunização , Vírus da Influenza A Subtipo H1N1/metabolismo , Vírus da Influenza A Subtipo H1N1/fisiologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/química , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia
19.
Drugs ; 79(4): 353-364, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30762205

RESUMO

Myasthenia gravis is a rare, heterogeneous, classical autoimmune disease characterized by fatigable skeletal muscle weakness, which is directly mediated by autoantibodies targeting various components of the neuromuscular junction, including the acetylcholine receptor, muscle specific tyrosine kinase, and lipoprotein-related protein 4. Subgrouping of myasthenia gravis is dependent on the age of onset, pattern of clinical weakness, autoantibody detected, type of thymic pathology, and response to immunotherapy. Generalized immunosuppressive therapies are effective in all subgroups of myasthenia gravis; however, approximately 15% remain refractory and more effective treatments with improved safety profiles are needed. In recent years, successful utilization of targeted B-cell therapies in this disease has triggered renewed focus in unraveling the underlying immunopathology in attempts to identify newer therapeutic targets. While myasthenia gravis is predominantly B-cell mediated, T cells, T cell-B cell interactions, and B-cell-related factors are increasingly recognized to play key roles in its immunopathology, particularly in autoantibody production, and novel therapies have focused on targeting these specific immune system components. This overview describes the current understanding of myasthenia gravis immunopathology before discussing B-cell-related therapies, their therapeutic targets, and the rationale and evidence for their use. Several prospective studies demonstrated efficacy of rituximab in various myasthenia gravis subtypes, particularly that characterized by antibodies against muscle-specific tyrosine kinase. However, a recent randomized control trial in patients with acetylcholine receptor antibodies was negative. Eculizumab, a complement inhibitor, has recently gained regulatory approval for myasthenia gravis based on a phase III trial that narrowly missed its primary endpoint while achieving robust results in all secondary endpoints. Zilucoplan is a subcutaneously administered terminal complement inhibitor that recently demonstrated significant improvements in functional outcome measures in a phase II trial. Rozanolixizumab, CFZ533, belimumab, and bortezomib are B-cell-related therapies that are in the early stages of evaluation in treating myasthenia gravis. The rarity of myasthenia gravis, heterogeneity in its clinical manifestations, and variability in immunosuppressive regimens are challenges to conducting successful trials. Nonetheless, these are promising times for myasthenia gravis, as renewed research efforts provide novel insights into its immunopathology, allowing for development of targeted therapies with increased efficacy and safety.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos B/efeitos dos fármacos , Imunossupressores/uso terapêutico , Miastenia Gravis/terapia , Anticorpos Monoclonais Humanizados/efeitos adversos , Antagonistas Colinérgicos/uso terapêutico , Inativadores do Complemento/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Imunoterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Colinérgicos/metabolismo
20.
Clin Exp Rheumatol ; 37 Suppl 118(3): 159-166, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30652677

RESUMO

OBJECTIVES: Glucocorticoids induce prompt clinical improvement in patients with IgG4-related disease (IgG4-RD) but their mechanisms of action in this specific condition are not fully understood. B lymphocytes appear central to IgG4-RD pathogenesis because B-cell depletion with rituximab leads to swift clinical responses. In the present work we aim to assess the effects of glucocorticoids on B-cell subpopulations in patients with IgG4-RD. METHODS: Fifty patients with active untreated IgG4-RD and 20 healthy controls were enrolled in the present study. Flow cytometry analysis for total circulating CD19+ and CD20+ cells, naïve B cells, memory B cells, plasmablasts, and plasma cells was performed at baseline in all patients, and after 6 months of glucocorticoid treatment in 30 patients. Correlation studies with biomarkers of disease activity were also performed. RESULTS: At baseline, patients with IgG4-RD showed reduced CD19+ and CD20+ B cells compared to healthy controls, but increased circulating plasmablasts and plasma cells. Circulating plasmablasts and plasma cells correlated with clinical and serological biomarkers of IgG4-RD activity. Glucocorticoid-induced disease remission was accompanied by a reduction of naïve B cell count, an increase of memory B cells, and by a depletion of circulating plasmablasts and plasma cells. CD19+ and CD20+ B cells, were not affected by glucocorticoids. CONCLUSIONS: The efficacy of glucocorticoids in IgG4-RD is associated with selective effects on different B-cell subpopulations. Further studies are warranted to fully understand possible perturbations of the naïve and memory B-cell compartments in patients with IgG4-RD.


Assuntos
Linfócitos B/efeitos dos fármacos , Glucocorticoides , Doença Relacionada a Imunoglobulina G4 , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G , Doença Relacionada a Imunoglobulina G4/sangue , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Doença Relacionada a Imunoglobulina G4/imunologia , Plasmócitos , Indução de Remissão
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