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1.
Viruses ; 12(9)2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967229

RESUMO

As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.


Assuntos
Fatores Imunológicos/imunologia , Viroses/imunologia , Vírus/imunologia , Animais , Antivirais/uso terapêutico , Doença Crônica , Humanos , Fatores Imunológicos/antagonistas & inibidores , Imunoterapia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Viroses/terapia , Vírus/classificação
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 673-679, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958122

RESUMO

Objective To investigate the therapeutic effect and mechanism of paeoniflorin on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) mice. Methods C57BL/6 male mice were randomly divided into control group, model group, 600 mg/(kg.d) mesalazine treatment group, (12.5, 25, 50) mg/(kg.d) paeoniflorin treatment group, with 10 mice in each. All mice were treated with 30 g/L DSS for 5 days except the control group. Meanwhile, the mice in the other groups were orally administrated corresponding drugs for 10 days, while the mice in the control and model groups were given equivalent volumes of distilled water. Body mass, fecal characteristics and hematochezia of the mice were observed and recorded daily, and then disease activity index (DAI) was evaluated and calculated. Pathological changes in the colon were observed by HE staining. The levels of anti-flagellin antibody, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in the serum were measured by ELISA. The expression levels of Toll-like receptor 5 (TLR5), myeloid differentiation factor 88 (MyD88) and nuclear factor kappa-Bp65 (NF-κBp65) in the colon tissues were evaluated by Western blot analysis and the activation of lymphocytes in mesenteric lymph node (MLN) was detected by flow cytometry. Results Compared with the control group, DAI scores in the model group were significantly raised, the colon length was significantly shortened, and the epithelium and intestinal gland disappeared. In addition, the serum levels of anti-flagellin antibody, IL-6, TNF-α and the protein levels of TLR5, MyD88, NF-κBp65 in the colon significantly increased, and the activation of T lymphocytes in MLN went up in the model group. All symptoms above were alleviated in the mesalazine and paeoniflorin groups compared with the model group. Conclusion Paeoniflorin can attenuate UC in mice by inhibiting the expression of flagellin and TLR5, and the activation of T cells.


Assuntos
Colite Ulcerativa , Glucosídeos , Ativação Linfocitária , Monoterpenos , Linfócitos T , Receptor 5 Toll-Like , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo/efeitos dos fármacos , Sulfato de Dextrana/toxicidade , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoterpenos/farmacologia , Monoterpenos/uso terapêutico , Distribuição Aleatória , Linfócitos T/efeitos dos fármacos , Receptor 5 Toll-Like/genética
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.
PLoS One ; 15(9): e0239516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956398

RESUMO

Intense dance training leads to inflammation, which may impair the health and performance of the practitioners. Herein, we evaluate the effect of a single street dancing class on the profile of muscle enzymes, lymphocyte activation, and cell surface CD62L expression. We also investigated the correlation between muscle enzymes, adhesion molecules, and lymphocyte activation in dancers. Fifteen male participants (mean ± standard error: age 22.4 ± 1.08 years, body mass index 24.8 ± 0.69 kg/m2, body fat 12.3 ± 1.52%), who were amateur dancers, had blood samples collected previously and subsequent to a high-intensity street dance class. After the class, dancers showed an increase in total lymphocyte count (2.0-fold), creatine kinase (CK)-NAC (4.87%), and CK-MB (3.36%). We also observed a decrease (2.5-fold) in reactive oxygen species (ROS) produced by lymphocytes, under phorbol myristate acetate-stimulated environments. Following the dance class, CD62L expression in lymphocytes decreased (51.42%), while there was a negative correlation between the intensity of the exercise and CD62L expression (r = -0.73; p = 0.01). Lymphocytes were less responsive to stimuli after a single bout of street dancing, indicating transient immunosuppression.


Assuntos
Dança/fisiologia , Selectina L/análise , Ativação Linfocitária , Creatina Quinase Forma MB/sangue , Dança/educação , Frequência Cardíaca , Humanos , Inflamação , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Espécies Reativas de Oxigênio/sangue , Acetato de Tetradecanoilforbol/farmacologia , Adulto Jovem
5.
PLoS One ; 15(9): e0238575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941476

RESUMO

OBJECTIVE: Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. DESIGN: Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. METHODS: We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks. RESULTS: Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of CD28-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. CONCLUSIONS: The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. CLINICAL TRIALS REGISTRATION: NCT02577042.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Raltegravir Potássico/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Feminino , Infecções por HIV/sangue , Infecções por HIV/imunologia , Inibidores da Protease de HIV/administração & dosagem , Humanos , Imunossenescência/efeitos dos fármacos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Raltegravir Potássico/administração & dosagem
6.
Orv Hetil ; 161(35): 1483-1487, 2020 08.
Artigo em Húngaro | MEDLINE | ID: mdl-32822327

RESUMO

Today, insulin hypersensitivity reactions are rare side effects of insulin therapy. In two-thirds of the suspected insulin allergy cases, the clinical symptoms are not related to insulin. The authors report the case of a 64-year-old female patient, by whom lymphocyte tarnsformation test (LTT) has been used to elucidate the background of allergic symptoms developed during insulin therapy. The performed LTT did not support hypersensitivity to insulin, however, the positive protamine test raised the suspicion of fish allergy. Complementary immunoserology also highlighted the coexistence of previously unrevealed thyroid disease. To our knowledge, this is the first documented case report in Hungary that attempts to address the real cause of a suspected hypersensitivity reaction to insulin by using LTT. Orv Hetil. 2020; 161(35): 1483-1487.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipersensibilidade a Drogas/complicações , Insulina/efeitos adversos , Ativação Linfocitária/efeitos dos fármacos , Hipersensibilidade a Drogas/diagnóstico , Feminino , Humanos , Hungria , Insulina/administração & dosagem , Pessoa de Meia-Idade
7.
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
8.
Expert Opin Biol Ther ; 20(9): 1025-1031, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32700604

RESUMO

INTRODUCTION: The globally rampant SARS CoV-2 pandemic requires novel medical strategies to control the severity of disease and death due to complications. Of the 15-20% patients that develop pulmonary symptoms, a sub-set develops an acute respiratory distress syndrome (ARDS) rapidly progressing into a critical condition. Marked elevation of cytokines/chemokines is observed with elevation of additional markers of inflammation, coagulation, and organ damage such as CRP, D-dimer, LDH, Ferritin and Troponin-I. This hyperinflammation leads to worsening of oxygen saturation due to pulmonary infiltration and exudation, organ damage, and dysfunction of coagulation pathway and may lead to multi-organ failure. AREAS COVERED: The role of anti-inflammatory monoclonal antibodies such as Itolizumab, in cytokine storm. EXPERT OPINION: Itolizumab, an anti-CD6 humanized IgG1 mAb, binds to domain-1 of CD-6 that is responsible for priming, activation, and differentiation of T-cells. Itolizumab significantly reduces T-cell proliferation along with substantial downregulation of the production of cytokines/chemokines. Approved for moderate to severe chronic plaque psoriasis in 2013 it is currently being studied for addressing COVID-19 related cytokine storm and its complications. This article reviews its use in COVID-19 infections; its dose, administration protocol, contra-indications, and safety in treating moderate-to-severe ARDS by preventing and treating the cytokine storm and its complications.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/fisiologia , Pandemias , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento
9.
Front Immunol ; 11: 1311, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32676080

RESUMO

Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.


Assuntos
Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Interferon gama/genética , Interleucina-17/genética , Inibidores de Janus Quinases/uso terapêutico , Pneumonia Viral/patologia , Pirazóis/uso terapêutico , Animais , Células Cultivadas , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/sangue , Citocinas/imunologia , Antígeno HLA-DR3/genética , Intestino Delgado/imunologia , Intestino Delgado/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Knockout , Pandemias , Pneumonia Viral/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/imunologia
10.
In Vivo ; 34(3 Suppl): 1593-1596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-536995

RESUMO

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Liases de Carbono-Enxofre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Metionina/metabolismo , Pneumonia Viral/tratamento farmacológico , Capuzes de RNA/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Administração Oral , Antivirais/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/uso terapêutico , Betacoronavirus/fisiologia , Liases de Carbono-Enxofre/administração & dosagem , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Metanálise como Assunto , Metilação/efeitos dos fármacos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pseudomonas putida/enzimologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , S-Adenosilmetionina/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacos
11.
Cancer Immunol Immunother ; 69(11): 2291-2303, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32504247

RESUMO

Target expression heterogeneity and the presence of an immunosuppressive microenvironment can hamper severely the efficiency of immunotherapeutic approaches. We have analyzed the potential to encounter and overcome such conditions by a combinatory two-target approach involving a bispecific antibody retargeting T cells to tumor cells and tumor-directed antibody-fusion proteins with costimulatory members of the B7 and TNF superfamily. Targeting the tumor-associated antigens EpCAM and EGFR with the bispecific antibody and costimulatory fusion proteins, respectively, we analyzed the impact of target expression and the influence of the immunosuppressive factors IDO, IL-10, TGF-ß, PD-1 and CTLA-4 on the targeting-mediated stimulation of T cells. Here, suboptimal activity of the bispecific antibody at diverse EpCAM expression levels could be effectively enhanced by targeting-mediated costimulation by B7.1, 4-1BBL and OX40L in a broad range of EGFR expression levels. Furthermore, the benefit of combined costimulation by B7.1/4-1BBL and 4-1BBL/OX40L was demonstrated. In addition, the expression of immunosuppressive factors was shown in all co-culture settings, where blocking of prominent factors led to synergistic effects with combined costimulation. Thus, targeting-mediated costimulation showed general promise for a broad application covering diverse target expression levels, with the option for further selective enhancement by the identification and blockade of main immunosuppressive factors of the particular tumor environment.


Assuntos
Anticorpos Biespecíficos/imunologia , Antígenos de Neoplasias/imunologia , Molécula de Adesão da Célula Epitelial/imunologia , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T/imunologia , Anticorpos Biespecíficos/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Linfócitos T/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188384, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531324

RESUMO

Cancer regression often fails after systemic immune activation, especially for solid tumors due to their local immunosuppressive microenvironments. Among these, the pancreatic cancer microenvironment is unique and an important reason for resistance to anti-cancer treatments that include immunotherapy. In this review, the three main "BAD" characteristics that create and maintain this immunosuppressive microenvironment are discussed for effector T cells: Barriers to overcome, Attraction problems, and their Disabilities. These inhibit both effector T-cell activation and infiltration, reducing immunotherapy effectiveness. Combination approaches for killing the "BAD" aim to normalize the tumor microenvironment and are recommended to enhance anti-cancer immune-system efficacy in pancreatic cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/efeitos dos fármacos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
13.
In Vivo ; 34(3 Suppl): 1593-1596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503816

RESUMO

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Liases de Carbono-Enxofre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Metionina/metabolismo , Pneumonia Viral/tratamento farmacológico , Capuzes de RNA/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Administração Oral , Antivirais/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/uso terapêutico , Betacoronavirus/fisiologia , Liases de Carbono-Enxofre/administração & dosagem , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Metanálise como Assunto , Metilação/efeitos dos fármacos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pseudomonas putida/enzimologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , S-Adenosilmetionina/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacos
14.
Nat Commun ; 11(1): 3196, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581215

RESUMO

T-cell bispecific antibodies (TCBs) crosslink tumor and T-cells to induce tumor cell killing. While TCBs are very potent, on-target off-tumor toxicity remains a challenge when selecting targets. Here, we describe a protease-activated anti-folate receptor 1 TCB (Prot-FOLR1-TCB) equipped with an anti-idiotypic anti-CD3 mask connected to the anti-CD3 Fab through a tumor protease-cleavable linker. The potency of this Prot- FOLR1-TCB is recovered following protease-cleavage of the linker releasing the anti-idiotypic anti-CD3 scFv. In vivo, the Prot-FOLR1-TCB mediates antitumor efficacy comparable to the parental FOLR1-TCB whereas a noncleavable control Prot-FOLR1-TCB is inactive. In contrast, killing of bronchial epithelial and renal cortical cells with low FOLR1 expression is prevented compared to the parental FOLR1-TCB. The findings are confirmed for mesothelin as alternative tumor antigen. Thus, masking the anti-CD3 Fab fragment with an anti-idiotypic mask and cleavage of the mask by tumor-specific proteases can be applied to enhance specificity and safety of TCBs.


Assuntos
Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/metabolismo , Complexo CD3/imunologia , Receptor 1 de Folato/imunologia , Peptídeo Hidrolases/metabolismo , Linfócitos T/imunologia , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/uso terapêutico , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/imunologia , Humanos , Imunoterapia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Terapia de Alvo Molecular , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Postgrad Med ; 132(7): 604-613, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32496926

RESUMO

Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading worldwide. Antiviral therapy is the most important treatment for COVID-19. Among the drugs under investigation, anti-malarials, chloroquine (CQ) and hydroxychloroquine (HCQ), are being repurposed as treatment for COVID-19. CQ/HCQ were shown to prevent receptor recognition by coronaviruses, inhibit endosome acidification, which interferes with membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. A number of in vitro studies revealed inhibitory effects of CQ/HCQ on various coronaviruses, including SARS-CoV-2 although conflicting results exist. Several clinical studies showed that CQ/HCQ alone or in combination with a macrolide may alleviate the clinical symptoms of COVID-19, promote viral conversion, and delay disease progression, with less serious adverse effects. However, recent studies indicated that the use of CQ/HCQ, alone or in combination with a macrolide, did not show any favorable effect on patients with COVID-19. Adverse effects, including prolonged QT interval after taking CQ/HCQ, may develop in COVID-19 patients. Therefore, current data are not sufficient enough to support the use of CQ/HCQ as therapies for COVID-19 and increasing caution should be taken about the application of CQ/HCQ in COVID-19 before conclusive findings are obtained by well-designed, multi-center, randomized, controlled studies.


Assuntos
Antivirais/uso terapêutico , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Cloroquina/farmacologia , Coronavirus Humano 229E/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Glicosilação , Humanos , Hidroxicloroquina/farmacologia , Imunidade Inata , Técnicas In Vitro , Síndrome do QT Longo/induzido quimicamente , Ativação Linfocitária/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Espécies Reativas de Oxigênio , Vírus da SARS/efeitos dos fármacos , Transdução de Sinais , Linfócitos T , Receptores Toll-Like/efeitos dos fármacos , Receptores Toll-Like/metabolismo , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
18.
Nat Chem Biol ; 16(7): 731-739, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32393898

RESUMO

Glucose is catabolized by two fundamental pathways, glycolysis to make ATP and the oxidative pentose phosphate pathway to make reduced nicotinamide adenine dinucleotide phosphate (NADPH). The first step of the oxidative pentose phosphate pathway is catalyzed by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here we develop metabolite reporter and deuterium tracer assays to monitor cellular G6PD activity. Using these, we show that the most widely cited G6PD antagonist, dehydroepiandosterone, does not robustly inhibit G6PD in cells. We then identify a small molecule (G6PDi-1) that more effectively inhibits G6PD. Across a range of cultured cells, G6PDi-1 depletes NADPH most strongly in lymphocytes. In T cells but not macrophages, G6PDi-1 markedly decreases inflammatory cytokine production. In neutrophils, it suppresses respiratory burst. Thus, we provide a cell-active small molecule tool for oxidative pentose phosphate pathway inhibition, and use it to identify G6PD as a pharmacological target for modulating immune response.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucosefosfato Desidrogenase/antagonistas & inibidores , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Via de Pentose Fosfato/efeitos dos fármacos , Animais , Linhagem Celular , Desidroepiandrosterona/farmacologia , Relação Dose-Resposta a Droga , Ensaios Enzimáticos , Glucose/metabolismo , Glucosefosfato Desidrogenase/imunologia , Glucosefosfato Desidrogenase/metabolismo , Glicólise/imunologia , Células HCT116 , Células Hep G2 , Humanos , Imunidade Inata , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/enzimologia , Linfócitos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/enzimologia , Macrófagos/imunologia , NADP/antagonistas & inibidores , NADP/metabolismo , Neutrófilos/citologia , Neutrófilos/enzimologia , Neutrófilos/imunologia , Via de Pentose Fosfato/imunologia
19.
Nat Commun ; 11(1): 1801, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286271

RESUMO

Naïve CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. Here we use quantitative proteomics, bulk RNA-seq, and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to show that responses to cytokines differ substantially between these cell types. Memory T cells are unable to differentiate into the Th2 phenotype, and acquire a Th17-like phenotype in response to iTreg polarization. Single-cell analyses show that T cells constitute a transcriptional continuum that progresses from naïve to central and effector memory T cells, forming an effectorness gradient accompanied by an increase in the expression of chemokines and cytokines. Finally, we show that T cell activation and cytokine responses are influenced by the effectorness gradient. Our results illustrate the heterogeneity of T cell responses, furthering our understanding of inflammation.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citocinas/farmacologia , Análise de Célula Única , Transcriptoma/genética , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Proteoma/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transcriptoma/efeitos dos fármacos
20.
PLoS One ; 15(4): e0227734, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298302

RESUMO

Both conventional and regulatory CD4+ T-cells rely on costimulatory signals mediated by cell surface receptors including CD28 for full activation. We showed previously that stimulation of CD4+ Foxp3+ regulatory T-cells by superagonistic anti-CD28 monoclonal antibodies (mAb) improves myocardial healing after experimental myocardial infarction (MI). However, the effect of ligand binding blocking anti-CD28 monoclonal antibodies has not yet been tested in this context. We hypothesize that ligand blocking anti-CD28 mAb treatment might favorably impact on healing after MI by limiting the activation of conventional CD4+ T-cells. Therefore, we studied the therapeutic effect of the recently characterized mAb E18 which blocks ligand binding to CD28 in a mouse permanent coronary ligation model. E18 or an irrelevant control mAb was applied once on day two after myocardial infarction to wildtype mice. Echocardiography was performed on day 7 after MI. E18 treatment improved the survival and reduced the incidence of left ventricular ruptures after experimental myocardial infarction. Accordingly, although we found no difference in infarct size, there was significantly less left ventricular dilation after E18 treatment in surviving animals as determined by echocardiography at day 7 after MI. In sham operated control mice neither antibody had an impact on body weight, survival, and echocardiographic parameters. Mechanistically, compared to control immunoglobulin, E18 treatment reduced the number of CD4+ T-cells and monocytes/macrophages within the infarct and periinfarct zone on day 5. This was accompanied by an upregulation of arginase which is a marker for alternatively differentiated macrophages. The data indicate that CD28-dependent costimulation of CD4+ T-cells impairs myocardial healing and anti-CD28 antibody treatment constitutes a potentially clinically translatable approach to improve the outcome early after MI.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD28/antagonistas & inibidores , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Arginase/imunologia , Arginase/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Humanos , Ligantes , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/patologia
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