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1.
Phytomedicine ; 80: 153381, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33086170

RESUMO

BACKGROUND: Hyperactivation of B cells by activators has been demonstrated to play a central role in the pathogenesis of Sjögren's syndrome (SS). In this study, we found that artesunate (ART) can attenuate BAFF-induced B cell hyperactivation and SS-like symptoms in NOD/Ltj mice. PURPOSE: To determine the efficacy of ART in attenuating SS-like symptoms in vivo and explore the underlying mechanism in vitro. STUDY DESIGN: ART was intragastrically injected into SS-like NOD/Ltj mice. The cytokine hsBAFF was used to activate Raji and Daudi B cells to mimic B cell hyperactivation in vitro. METHODS: The efficacy of ART in inhibiting SS progression was studied in NOD/Ltj mice. Salivary flow rate, the number of lymphocytic infiltration foci, the level of autoantibodies and the extent of B cell infiltration were measured in the indicated groups. CCK-8 assays, flow cytometry-based EdU staining and Annexin V/PI staining were also used to detect the effect of ART on the survival and proliferation mechanism in BAFF-induced Raji and Daudi cells. Further studies determined that TRAF6 degradation is a potential mechanism by which ART determines B cell fate. RESULTS: Treatment with ART inhibited lymphocytic foci formation, B cell infiltration and autoantibody secretion in SS-like NOD/Ltj mice. In vitro assay results indicated that ART effectively inhibited BAFF-induced viability, survival and proliferation of neoplastic B cells. Mechanistically, ART targeted BAFF-activated NFκB by regulating the proteasome-mediated degradation of TRAF6 in Raji and Daudi cells. CONCLUSION: ART ameliorated murine SS-like symptoms and regulated TRAF6-NFκB signaling, thus determining survival and proliferation of B cells.


Assuntos
Artesunato/farmacologia , Fator Ativador de Células B/farmacologia , Linfócitos B/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Síndrome de Sjogren/imunologia , Animais , Autoanticorpos/metabolismo , Autoimunidade/efeitos dos fármacos , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos ICR , Camundongos Endogâmicos NOD , NF-kappa B/metabolismo , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/patologia
2.
J Neuroimmunol ; 349: 577402, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32977248

RESUMO

B cells play a major role in the pathophysiology of myasthenia gravis (MG) with their ability to produce disease specific, pathogenic antibodies. However, their status during disease development and follow-up stages of the disease in the peripheral blood may need further studies to determine useful markers. In this study, we aimed to detect B cell associated factors concerning immunosuppressive treatment in generalized non-thymomatous MG patients. Although CD19+ B cell distribution did not vary among disease subgroups, expressions of both CD38 and BAFFR were altered on B cells in MG patients under immunosuppressive therapy. Serum levels of BAFF were elevated in untreated MG patients as compared to treated MG patients and healthy controls. B cell activation factors may show profound alterations due to immunosuppression.


Assuntos
Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Imunossupressores/uso terapêutico , Miastenia Gravis/sangue , Miastenia Gravis/tratamento farmacológico , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Criança , Feminino , Humanos , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/diagnóstico , Resultado do Tratamento , Adulto Jovem
3.
PLoS One ; 15(9): e0222548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32870913

RESUMO

The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) regulates nuclear-factor-kappa-B (NF-κB) activation downstream of surface receptors with immunoreceptor tyrosine-based activation motifs (ITAMs), such as the B-cell or T-cell receptor and has thus emerged as a therapeutic target for autoimmune diseases. However, recent reports demonstrate the development of lethal autoimmune inflammation due to the excessive production of interferon gamma (IFN-É£) and defective differentiation of regulatory T-cells in genetically modified mice deficient in MALT1 paracaspase activity. To address this issue, we explored the effects of pharmacological MALT1 inhibition on the balance between T-effector and regulatory T-cells. Here we demonstrate that allosteric inhibition of MALT1 suppressed Th1, Th17 and Th1/Th17 effector responses, and inhibited T-cell dependent B-cell proliferation and antibody production. Allosteric MALT1 inhibition did not interfere with the suppressive function of human T-regulatory cells, although it impaired de novo differentiation of regulatory T-cells from naïve T-cells. Treatment with an allosteric MALT1 inhibitor alleviated the cytokine storm, including IFN-É£, in a mouse model of acute T-cell activation, and long-term treatment did not lead to an increase in IFN-É£ producing CD4 cells or tissue inflammation. Together, our data demonstrate that the effects of allosteric inhibition of MALT1 differ from those seen in mice with proteolytically inactive MALT1, and thus we believe that MALT1 is a viable target for B and T-cell driven autoimmune diseases.


Assuntos
Linfócitos B/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Feminino , Transferência Ressonante de Energia de Fluorescência , Voluntários Saudáveis , Humanos , Injeções Intraperitoneais , Interferon gama/imunologia , Interferon gama/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Fenotiazinas/farmacologia , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo
4.
Sci Rep ; 10(1): 13212, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764544

RESUMO

IL-35 is an anti-inflammatory cytokine and is thought to be produced by regulatory T (Treg) cells. A previous study found that IL-35 was upregulated in the serum of patients with active tuberculosis (ATB), and IL-35-producing B cells infiltrated to tuberculous granuloma of patients with ATB. Purified B cells from such patients generated more IL-35 after stimulation by antigens of Mycobacterium tuberculosis and secreted more IL-10. However, the function and the underlying mechanisms of IL-35-producing B cells in TB progression have not been investigated. The present study found that the expression of mRNA of IL-35 subsets Ebi3 and p35 was elevated in mononuclear cells from peripheral blood, spleen, bone marrow, and lung tissue in a mouse model infected with Mycobacterium bovis BCG, as tested by real-time polymerase chain reaction. Accordingly, the flow cytometry analysis showed that the counts of a subset of IL-35+ B cells were elevated in the circulating blood and in the spleen, bone marrow, and lung tissue in BCG-infected mice, whereas anti-TB therapy reduced IL-35-producing B cells. Interestingly, BCG infection could drive the infiltration of IL-35-producing B cells into the lung tissue, and the elevated counts of IL-35-producing B cells positively correlated with the bacterial load in the lungs. Importantly, the injection of exogenous IL-35 stimulated the elevation in the counts of IL-35-producing B cells and was associated with the downregulation of Th1/Th17 and upregulation of Foxp3+Treg.The study showed that a subset of IL-35-producing B cells might take part in the downregulation of immune response in mycobacterial infection.


Assuntos
Linfócitos B/imunologia , Interleucinas/metabolismo , Pulmão/imunologia , Mycobacterium bovis , Linfócitos T Reguladores/imunologia , Tuberculose Pulmonar/imunologia , Animais , Antituberculosos/farmacologia , Linfócitos B/efeitos dos fármacos , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Interleucina-10/metabolismo , Interleucinas/genética , Pulmão/microbiologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Tuberculose Pulmonar/metabolismo , Regulação para Cima
5.
Nat Commun ; 11(1): 3924, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764665

RESUMO

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Monócitos/imunologia , Pneumonia Viral/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Biologia Computacional , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/sangue , Humanos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Receptores de Interleucina-6/imunologia , Análise de Célula Única/métodos
6.
Cancer Invest ; 38(8-9): 463-475, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32772580

RESUMO

In the present study, we searched selective cytotoxicity and mitochondria mediated apoptosis of novel COX-2 inhibitor 2-(4-(Methylsulfonyl)phenyl)imidazo[1,2-a] pyridine-8-carboxylic acid on B-lymphocytes and their mitochondria isolated from normal subjects and acute lymphoblastic leukemia (ALL) patients' blood. Our results showed this compound can selectively induce cellular and mitochondrial toxicity on ALL B-lymphocytes and mitochondria without any toxic effects on normal B-lymphocytes and their mitochondria. Taken together, the results of this study suggest that cancerous mitochondria are a potential target for the ALL B-lymphocytes. Selective toxicity of COX-2 inhibitor in cancerous mitochondria could be an attractive therapeutic option for the effective clinical management of therapy-resistant ALL.


Assuntos
Linfócitos B/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Mitocôndrias/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos B/patologia , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Citocromos c/metabolismo , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/enzimologia , Membranas Mitocondriais/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/metabolismo
7.
J Virol ; 94(21)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796077

RESUMO

Epstein-Barr virus (EBV) is one of nine human herpesviruses that persist latently to establish permanent residence in their hosts. Periodic activation into the lytic/replicative phase allows such viruses to propagate and spread, but can also cause disease in the host. This lytic phase is also essential for EBV to cause infectious mononucleosis and cancers, including B lymphocyte-derived Burkitt lymphoma and immunocompromise-associated lymphoproliferative diseases/lymphomas as well as epithelial cell-derived nasopharyngeal cell carcinoma. In the absence of anti-EBV agents, however, therapeutic options for EBV-related diseases are limited. In earlier work, we discovered that through the activities of the viral protein kinase conserved across herpesviruses and two cellular proteins, ATM and KAP1, a lytic cycle amplification loop is established, and disruption of this loop disables the EBV lytic cascade. We therefore devised a high-throughput screening assay, screened a small-molecule-compound library, and identified 17 candidates that impair the release of lytically replicated EBV. The identified compounds will (i) serve as lead compounds or may be modified to inhibit EBV and potentially other herpesviruses, and (ii) be developed into anticancer agents, as functions of KAP1 and ATM are tightly linked to cancer. Importantly, our screening strategy may also be used to screen additional compound libraries for antiherpesviral and anticancer drugs.IMPORTANCE Epstein-Barr virus, which is nearly ubiquitous in humans, is causal to infectious mononucleosis, chronic active EBV infection, and lymphoid and epithelial cancers. However, EBV-specific antiviral agents are not yet available. To aid in the identification of compounds that may be developed as antivirals, we pursued a mechanism-based approach. Since many of these diseases rely on EBV's lytic phase, we developed a high-throughput assay that is able to measure a key step that is essential for successful completion of EBV's lytic cascade. We used this assay to screen a library of small-molecule compounds and identified inhibitors that may be pursued for their anti-EBV and possibly even antiherpesviral potential, as this key mechanism appears to be common to several human herpesviruses. Given the prominent role of this mechanism in both herpesvirus biology and cancer, our screening assay may be used as a platform to identify both antiherpesviral and anticancer drugs.


Assuntos
Antivirais/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Herpesvirus Humano 4/efeitos dos fármacos , Proteínas Quinases/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Transativadores/genética , Proteína 28 com Motivo Tripartido/genética , Antivirais/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/virologia , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/patologia , Linfoma de Burkitt/virologia , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Regulação da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/metabolismo , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Lisogenia/efeitos dos fármacos , Fosforilação , Proteínas Quinases/metabolismo , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/química , Transativadores/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Replicação Viral
8.
Hematol Oncol ; 38(5): 705-714, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32822067

RESUMO

Alterations of B-cell lymphoma 2 (BCL-2) family proteins contribute to the survival of B-cell malignancies. Recently, venetoclax, a BCL-2 inhibitor, was approved for B-cell chronic lymphocytic leukemia therapy and is being investigated in clinical trials for a variety of hematologic cell malignancies. Furthermore, combination therapy with other molecularly targeted drugs was reported to be more effective than monotherapy. However, combining venetoclax with immunotherapy based on T-cells has not been tested. Because both venetoclax and granzyme B activate the mitochondrial apoptosis pathway by targeting different BCL-2 family molecules, it is possible that combinations of venetoclax with immunotherapy will be effective treatments. We examined the effect of combining venetoclax with immunotherapy using an in vitro model system involving cytomegalovirus (CMV) pp65 antigen-specific cytotoxic T-cells (CMV-CTLs) as the effector cells and CMVpp65 antigen-expressing B-cell lines as the target cells. Cytotoxicity of CMV-CTLs to the target B-cell lines was enhanced by venetoclax with combination index values of 0.47-0.83. This suggests that venetoclax synergizes with T-cell-based immunotherapy to affect B-cell malignancies. Interestingly, venetoclax synergized not only with antigen-specific cytotoxicity but also with nonspecific cytotoxicity. Importantly, CMV-CTLs could be expanded in the presence of venetoclax at the maximum concentration (5 µM) that induced apoptosis in resting CMV-CTLs. B-cell lymphoma-extra large (BCL-xL) expression in CMV-CTLs increased transiently after activation by CMVpp65-transfected B-cell lines, indicating that the expression of BCL-xL was important for the effectiveness of combination treatment with venetoclax. These findings suggest that T-cell-based immunotherapy combined with venetoclax is effective against B-cell malignancies.


Assuntos
Antineoplásicos/farmacologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Sulfonamidas/farmacologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Imunoterapia , Camundongos , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Proteínas da Matriz Viral/fisiologia
9.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L717-L727, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32845704

RESUMO

Most of electronic cigarette (e-cigarette) users are also smoking tobacco cigarettes. Because of the relative novelty of this habit, very little is known on the impact of vaping on pulmonary health, even less on the potential interactions of dual e-cigarette and tobacco cigarette use. Therefore, we used well-established mouse models to investigate the impact of dual exposure to e-cigarette vapors and tobacco cigarette smoke on lung homeostasis. Groups of female BALB/c mice were exposed to room air, tobacco smoke only, nicotine-free flavor-free e-cigarette vapors only or both tobacco smoke and e-cigarette vapors. Moreover, since tobacco smoke and electronic cigarette vapors both affect circadian processes in the lungs, groups of mice were euthanized at two different time points during the day. We found that dual-exposed mice had altered lung circadian gene expression compared with mice exposed to tobacco smoke alone. Dual-exposed mice also had different frequencies of dendritic cells, macrophages, and neutrophils in the lung tissue compared with mice exposed to tobacco smoke alone, an observation also valid for B-lymphocytes and CD4+ and CD8+ T lymphocytes. Exposure to e-cigarette vapors also impacted the levels of immunoglobulins in the bronchoalveolar lavage and serum. Finally, e-cigarette and dual exposures increased airway resistance compared with mice exposed to room air or tobacco smoke alone, respectively. Taken together, these data suggest that e-cigarette vapors, even without nicotine or flavors, could affect how the lungs react to tobacco cigarette smoke exposure in dual users, potentially altering the pathological course triggered by smoking.


Assuntos
Linfócitos B/efeitos dos fármacos , Vapor do Cigarro Eletrônico/efeitos adversos , Fumaça/efeitos adversos , Fumar/efeitos adversos , Animais , Sistemas Eletrônicos de Liberação de Nicotina , Pulmão/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Nicotina/metabolismo , Nicotina/farmacologia
10.
Immunity ; 53(4): 724-732.e7, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32783919

RESUMO

SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , RNA Mensageiro/imunologia , RNA Viral/imunologia , Vacinas Virais/administração & dosagem , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/virologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Modelos Animais de Doenças , Furina/genética , Furina/imunologia , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunização/métodos , Imunogenicidade da Vacina , Memória Imunológica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/química , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , RNA Mensageiro/genética , RNA Viral/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas , Vacinas Virais/biossíntese , Vacinas Virais/genética
11.
J Dtsch Dermatol Ges ; 18(8): 795-807, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32761894

RESUMO

The COVID-19 pandemic caused by SARS-CoV-2 has far-reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS-CoV-2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS-CoV-2/COVID-19 with mediators of the acute phase of inflammation (TNF, IL-1, IL-6), type 1 and type 17 immune responses (IL-12, IL-23, IL-17, IL-36), type 2 immune reactions (IL-4, IL-13, IL-5, IL-31, IgE), B-cell immunity, checkpoint regulators (PD-1, PD-L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non-specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte-mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS-CoV-2/COVID-19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID-19 pandemic; some even appear to alleviate COVID-19.


Assuntos
/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Síndrome da Liberação de Citocina/imunologia , Humanos , Imunoterapia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
12.
PLoS One ; 15(7): e0235743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645052

RESUMO

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.


Assuntos
Linfócitos B/imunologia , Granulomatose com Poliangiite , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Adulto , Idoso , Azatioprina/farmacologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/imunologia , Humanos , Interleucina-6/metabolismo , Masculino , Mercaptopurina/farmacologia , Pessoa de Meia-Idade
13.
PLoS One ; 15(7): e0235449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716916

RESUMO

BACKGROUND: Several disease modifying drugs (DMDs) have been approved for the treatment of multiple sclerosis (MS), however, little is known about their differential impact on peripheral blood (PB) B cell subsets. METHODS: We performed a cross sectional study on PB B cells in MS patients treated with interferon-ß (n = 25), glatiramer acetate (n = 19), dimethyl fumarate (n = 15), fingolimod (n = 16) or natalizumab (n = 22), untreated MS patients (n = 20), and in patients with non-inflammatory neurological diseases (n = 12). Besides analyzing routine laboratory data, flow cytometry was performed to analyze naïve B cells (CD19+CD20+CD27-IgD+), non-class switched (CD19+CD20+CD27+IgD+) and class-switched memory B cells (CD19+CD20+CD27+IgD-), double negative B cells (CD19+CD20lowCD27-IgD-) and plasmablasts (CD19+CD20lowCD27+CD38++). RESULTS: Treatment associated changes were found for the overall B cell pool as well as for all B cell subsets. Natalizumab increased absolute numbers and percentage of all B cells mainly by expanding the memory B cell pool. Fingolimod decreased absolute numbers of all B cell subsets and the percentage of total B cells. Fingolimod, dimethyl fumarate and interferon-ß treatments were associated with an increase in the fraction of naïve B cells while class switched and non-class switched memory B cells showed decreased percentages. CONCLUSION: Our results highlight differential effects of DMDs on the PB B cell compartment. Across the examined treatments, a decreased percentage of memory B cells was found in dimethyl fumarate, interferon-ß and fingolimod treated patients which might contribute to the drugs' mode of action in MS. Further studies are necessary to decipher the exact role of B cell subsets during MS pathogenesis.


Assuntos
Subpopulações de Linfócitos B/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/classificação , Antígenos CD/imunologia , Antígenos CD19 , Subpopulações de Linfócitos B/classificação , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Estudos Transversais , Fumarato de Dimetilo/administração & dosagem , Feminino , Cloridrato de Fingolimode/administração & dosagem , Citometria de Fluxo , Acetato de Glatiramer/administração & dosagem , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Interferon beta/administração & dosagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Natalizumab/administração & dosagem , Adulto Jovem
14.
Mol Immunol ; 125: 140-150, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32682148

RESUMO

Successful transplantation outcome is the final goal in most end stage and nonfunctional organs; however, despite using different therapeutic strategies, antibody-mediated rejection is still a big obstacle. B cells have a key role in transplant rejection by several functions, such as antibody production, antigen presenting, contribution in T cell activation, forming the germinal center, and tertiary lymphoid organs. Therefore, B cells modulation seems to be very crucial in transplant outcome. A double-edged sword function is considered for B cells during transplantation; On the one hand, antibody production against the transplanted organ induces antibody-mediated rejection. On the other hand, IL10 production by regulatory B (Breg) cells induces graft tolerance. Nowadays, several monoclonal antibodies (mAb) are available for B cell modulation that are routinely used in transplant recipients, among which rituximab (anti-CD20 mAb) act in eliminating B cells. However, there are some other monoclonal antibodies, such as epratuzumab and Inotuzumab ozogamicin (IO), which exert anti-CD22 activity, resulting in disruption of B cell functions and induction of tolerance in autoimmune disease or B cell malignancies; that notwithstanding, these mAbs have not yet been tried in transplantation. In this review, we focus on different methods for modulating the activity of B cells as well as induction of Breg cells, aiming to prevent the allograft rejection.


Assuntos
Anticorpos Monoclonais/farmacologia , Linfócitos B/efeitos dos fármacos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Tolerância ao Transplante/efeitos dos fármacos , Tolerância ao Transplante/imunologia , Animais , Linfócitos B/imunologia , Humanos , Transplante Homólogo
15.
Sci Rep ; 10(1): 12668, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728053

RESUMO

Interleukin-2 (IL-2) has both pro- and anti-inflammatory properties that have been harnessed clinically and that are used experimentally to modulate leukocyte subsets in vivo. In mice, the bioavailability and half-life of IL-2 in vivo can be increased by complexing recombinant IL-2 with different clones of anti-IL-2 monoclonal antibodies that differentially target the cytokine to cells expressing different kinds of IL-2 receptors. While the impacts of systemic IL-2: anti-IL-2 antibody complex (IL-2C) administration are well-defined in the spleen and peripheral lymph nodes, how immune cells in the gut and gut-associated lymphoid tissues respond to IL-2C is not well characterized. Here, we analyze how major leukocyte populations in these tissues respond to IL-2C. We find that IL-2C targeting cells expressing IL-2 receptor beta cause an acute decrease in cellularity of Peyer's Patches while cell numbers in the lamina propria and intraepithelial lymphocytes are unaffected. Cell contraction in Peyer's Patches is associated with the apoptosis of multiple B cell subsets. Our results are important to consider for understanding off-target impacts of IL-2C regimes in experimental models and for considering how IL-2 may contribute to the etiology or severity of gut-associated conditions such as Crohn's Disease.


Assuntos
Linfócitos B/citologia , Misturas Complexas/administração & dosagem , Subunidade beta de Receptor de Interleucina-2/metabolismo , Interleucina-2/metabolismo , Nódulos Linfáticos Agregados/citologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Disponibilidade Biológica , Sobrevivência Celular/efeitos dos fármacos , Misturas Complexas/farmacologia , Feminino , Meia-Vida , Interleucina-2/antagonistas & inibidores , Camundongos , Nódulos Linfáticos Agregados/efeitos dos fármacos , Nódulos Linfáticos Agregados/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia
16.
Sci Rep ; 10(1): 11676, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669656

RESUMO

This multicenter, randomized, double-blind, parallel-controlled trial aimed to compare the pharmacokinetics (PK) of IBI301 with rituximab in patients with CD20-positive (CD20+) B-cell lymphoma, who achieved a complete response/unconfirmed complete response after standard treatments. Patients were randomized (1:1) to receive IBI301 or rituximab (375 mg/m2, IV). Patients who continuously benefitted from the trial after the PK phase underwent the extension phase to receive up to three cycles of 3-month-cycle of rituximab/IBI301 maintenance therapy. PK was described using the area under the serum concentration-time curve from time zero to infinity (AUC0-inf), AUC from time zero to last quantifiable concentration (AUC0-t), and maximum serum concentration (Cmax). Pharmacodynamics (PD), incidence of adverse events and immunogenicity were evaluated. PK was defined equivalent, if 90% confidence intervals (CIs) for geometric mean ratios of PK endpoints fell within the margin of 0.8-1.25. Overall, 181 patients were enrolled in IBI301 (n = 89) and rituximab (n = 92) groups. Geometric mean ratios of AUC0-inf, AUC0-t, and Cmax were 0.91 (90% CI 0.85, 0.97), 0.91 (90% CI 0.86, 0.97), and 0.96 (90% CI 0.92, 1.01) between treatment groups, all within the bioequivalence range. Peripheral CD19+ and CD20+ B-cell counts were similar at each prespecified time point between the groups. No difference in immunogenicity was observed. The incidences of treatment-emergent adverse events (84.3% vs. 83.5%) and treatment-related AEs (56.2% vs. 61.5%) were comparable (IBI301 vs. rituximab). IBI301 was PK bioequivalent to rituximab in patients with CD20+ B-cell lymphoma. The PD, safety, and immunogenicity profiles of IBI301 were similar to those of rituximab.


Assuntos
Anticorpos Monoclonais/farmacocinética , Antígenos CD20/imunologia , Antineoplásicos Imunológicos/farmacocinética , Linfócitos B/efeitos dos fármacos , Linfoma de Células B/tratamento farmacológico , Rituximab/farmacocinética , Adulto , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacologia , Antígenos CD20/genética , Antineoplásicos Imunológicos/sangue , Antineoplásicos Imunológicos/farmacologia , Área Sob a Curva , Linfócitos B/imunologia , Linfócitos B/patologia , Disponibilidade Biológica , Medicamentos Biossimilares , Método Duplo-Cego , Feminino , Expressão Gênica , Humanos , Injeções Intravenosas , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Rituximab/sangue , Rituximab/farmacologia
18.
PLoS Pathog ; 16(4): e1008515, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32353085

RESUMO

Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.


Assuntos
Interferons/farmacologia , Receptores de Interferon/biossíntese , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Células Epiteliais/metabolismo , Expressão Gênica , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Interferon alfa-2/farmacologia , Interferons/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Processamento de RNA , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Viroses/genética , Viroses/imunologia , Viroses/metabolismo
20.
BMC Neurol ; 20(1): 202, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32438901

RESUMO

BACKGROUND: A high multiple sclerosis activity while on alemtuzumab is rather uncommon compared to moderate-efficacy drugs. The purpose of this case report is to present a case of a 37-year-old female patient with bronchial asthma and no other medical history, whose disease activity required switching from dimethyl fumarate to fingolimod, then to alemtuzumab and finally to ocrelizumab. CASE PRESENTATION: In our patient, two severe attacks were observed and treated after administration of the first pulse of alemtuzumab. After six months of therapy, patient's immunological profile showed the expected decrease in CD4+ and CD8+ T-cells and, markedly increased values of CD19+ B-cells. Surprisingly memory B-cells, which typically repopulate very slowly following alemtuzumab treatment, were above baseline levels. Regular administration of ocrelizumab based on a standardised scheme, after the alemtuzumab therapy failure, resulted in the stabilisation of the patient's condition both clinically and radiologically. CONCLUSION: Thus, when the alemtuzumab treatment is unsuccessful, the authors recommend testing T- and B-cell levels and proceeding with an early switch to ocrelizumab if high B-cell counts are found.


Assuntos
Alemtuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Falha de Tratamento , Adulto , Linfócitos B/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Humanos
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