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1.
Dtsch Med Wochenschr ; 144(12): 842-849, 2019 06.
Artigo em Alemão | MEDLINE | ID: mdl-31212328

RESUMO

Hospital-acquired Clostridium difficile infections have become much more frequent in recent years. Besides treatment with antibiotics and fecal microbiota transplant, new preventive strategies are available now. Bezlotoxumab is an antibody against toxin B and may reduce the risk of relapse by roughly 10 %. Several vaccine candidates against toxins A and B and surface-associated antigens were immunogenic and are tested in clinical trials to investigate the efficacy and safety.


Assuntos
Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Vacinas Bacterianas/uso terapêutico , Infecções por Clostridium , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Clostridium/imunologia , Infecções por Clostridium/microbiologia , Infecções por Clostridium/prevenção & controle , Infecções por Clostridium/terapia , Clostridium difficile/imunologia , Transplante de Microbiota Fecal , Humanos , Pessoa de Meia-Idade
3.
Nat Med ; 25(4): 547-553, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30936546

RESUMO

Combination anti-retroviral therapy (ART) has revolutionized the treatment and prevention of HIV-1 infection. Taken daily, ART prevents and suppresses the infection. However, ART interruption almost invariably leads to rebound viremia in infected individuals due to a long-lived latent reservoir of integrated proviruses. Therefore, ART must be administered on a life-long basis. Here we review recent preclinical and clinical studies suggesting that immunotherapy may be an alternative or an adjuvant to ART because, in addition to preventing new infections, anti-HIV-1 antibodies clear the virus, directly kill infected cells and produce immune complexes that can enhance host immunity to the virus.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/imunologia , Animais , Ensaios Clínicos como Assunto , Infecções por HIV/prevenção & controle , Humanos
4.
Nat Commun ; 10(1): 1953, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028254

RESUMO

Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection. We previously demonstrated a strong association between protection and merozoite-neutralizing antibody responses following vaccination of non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5). Here, we test the mechanism of protection. Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys. At the highest dose tested, 6/6 animals given the neutralizing PfRH5-binding mAb c2AC7 survive the challenge without treatment, compared to 0/6 animals given non-neutralizing PfRH5-binding mAb c4BA7 and 0/6 animals given an isotype control mAb. Our results address the controversy regarding whether merozoite-neutralizing antibody can cause protection against P. falciparum blood-stage infections, and highlight the quantitative challenge of achieving such protection.


Assuntos
Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antiprotozoários/imunologia , Humanos , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Vacinas Antimaláricas/uso terapêutico , Malária Falciparum/metabolismo , Plasmodium falciparum/imunologia , Plasmodium falciparum/patogenicidade , Primatas
5.
Int J Mol Sci ; 20(5)2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30823477

RESUMO

Increasing researches have focused on cancer metastasis and development. The ectonucleotidase CD73 is one of the most common cell surface enzymes that are involved in immunosuppression. In this study, the recombinant plasmid pET28a-CD73 was constructed and the CD73 protein was overexpressed in E. coli as an inclusion body that was then subjected to refolding. The anti-CD73 monoclonal antibody (3F7) was obtained by hybridoma technology. The antibody subtype was identified as IgG2a with an affinity constant of 5.75 nM. This antibody could be applied to immunofluorescence and flow cytometry. The results showed that the CD73 protein was not only located in the cytoplasm but also distributed on the surface of triple-negative breast cancer cells MDA-MB-231 and MDA-MB-468. Moreover, the level of CD73 protein was associated with the survival rate. Although the anti-CD73 antibody was not able to inhibit tumor cell growth, it could enhance the cytotoxic effect of Doxorubicin to triple-negative breast cancer cells. In vitro function assay results indicated that anti-CD73 mAb could inhibit cell migration and invasion in both human triple-negative breast cancer and mouse 4T1 cell lines. In this process, both the LC3I/LC3II ratio and p62 protein levels increased, which indicated that the blockage of CD73 could inhibit cell autophagy, and cell migration and invasion were restored by rapamycin. In vivo, anti-CD73 mAb could significantly inhibit lung metastasis of 4T1 cells in a mouse xenograft model. Taken together, this novel anti-CD73 antibody could be developed as an adjuvant drug for triple-negative breast cancer therapy and can be useful in tumor diagnosis.


Assuntos
5'-Nucleotidase/imunologia , Anticorpos Monoclonais/uso terapêutico , Autofagia , Movimento Celular/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , 5'-Nucleotidase/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
6.
N Engl J Med ; 380(19): 1825-1833, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-30883047

RESUMO

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P<0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.).


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Plaquetas/efeitos dos fármacos , Coagulantes/uso terapêutico , Inibidores da Agregação de Plaquetas , Ticagrelor/antagonistas & inibidores , Adulto , Anticorpos Neutralizantes/efeitos adversos , Plaquetas/fisiologia , Coagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico
7.
Int Immunopharmacol ; 69: 368-372, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30776645

RESUMO

The relationship between inflammation and formation of reactive oxygen species (ROS) is still not completely understood and excessive inflammatory reaction is attributed to increased yet also to reduced ROS formation. To compare ROS formation in severe and low inflammation, neutrophil oxidative burst was analyzed in rheumatic patients before and during therapy with TNFα- or interleukin-6 receptor-neutralizing antibodies. Intracellular and extracellular ROS productions were evaluated on the basis of luminol- and isoluminol-enhanced chemiluminescence in isolated peripheral neutrophils. Disease activity score DAS28 and platelet to lymphocyte ratio were used as markers of arthritis activity and the intensity of systemic inflammation. Biological therapy effectively reduced the intensity of inflammation. Of the twenty-six patients studied eighteen achieved remission or low disease activity. Highly active arthritis persisted only in one patient, though prior to the therapy it was evident in all subjects tested. In patients receiving biological therapy, intracellular chemiluminescence was significantly higher than in patients before this therapy; ROS produced by neutrophils extracellularly were not affected. The increased ROS formation associated with reduced inflammation supports the need to revise the view of the role of ROS in inflammation - from toxic agents promoting inflammation towards a more complex view of ROS as regulators of immune pathways with inflammation-limiting capacity. From this perspective, the interference with neutrophil-derived oxidants may represent a new mechanism involved in the anti-inflammatory activity of biological therapy.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoterapia/métodos , NADPH Oxidases/metabolismo , Neutrófilos/fisiologia , Adulto , Idoso , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Interleucina-6/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
8.
Nat Commun ; 10(1): 105, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631063

RESUMO

The 2013-2016 Ebola virus (EBOV) disease epidemic demonstrated the grave consequences of filovirus epidemics in the absence of effective therapeutics. Besides EBOV, two additional ebolaviruses, Sudan (SUDV) and Bundibugyo (BDBV) viruses, as well as multiple variants of Marburg virus (MARV), have also caused high fatality epidemics. Current experimental EBOV monoclonal antibodies (mAbs) are ineffective against SUDV, BDBV, or MARV. Here, we report that a cocktail of two broadly neutralizing ebolavirus mAbs, FVM04 and CA45, protects nonhuman primates (NHPs) against EBOV and SUDV infection when delivered four days post infection. This cocktail when supplemented by the anti-MARV mAb MR191 exhibited 100% efficacy in MARV-infected NHPs. These findings provide a solid foundation for clinical development of broadly protective immunotherapeutics for use in future filovirus epidemics.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Ebolavirus/imunologia , Infecções por Filoviridae/imunologia , Marburgvirus/imunologia , Doenças dos Primatas/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Ebolavirus/classificação , Ebolavirus/efeitos dos fármacos , Ebolavirus/fisiologia , Infecções por Filoviridae/terapia , Infecções por Filoviridae/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Imunoterapia/métodos , Marburgvirus/efeitos dos fármacos , Marburgvirus/fisiologia , Doenças dos Primatas/terapia , Doenças dos Primatas/virologia , Primatas , Resultado do Tratamento
9.
Viruses ; 11(2)2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678320

RESUMO

Zika virus (ZIKV) infection can cause severe congenital diseases, such as microcephaly, ocular defects and arthrogryposis in fetuses, and Guillain⁻Barré syndrome in adults. Efficacious therapeutic treatments for infected patients, as well as prophylactic treatments to prevent new infections are needed for combating ZIKV infection. Here, we report that ZIKV-specific human polyclonal antibodies (SAB-155), elicited in transchromosomal bovine (TcB), provide significant protection from infection by ZIKV in STAT2 knockout (KO) golden Syrian hamsters both prophylactically and therapeutically. These antibodies also prevent testicular lesions in this hamster model. Our data indicate that antibody-mediated immunotherapy is effective in treating ZIKV infection. Because suitable quantities of highly potent human polyclonal antibodies can be quickly produced from the TcB system against ZIKV and have demonstrated therapeutic efficacy in a small animal model, they have the potential as an effective countermeasure against ZIKV infection.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Imunização Passiva , Fator de Transcrição STAT2/genética , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/terapia , Animais , Animais Geneticamente Modificados , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Bovinos , Cricetinae , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Testículo/patologia , Testículo/virologia , Zika virus
10.
Cell Host Microbe ; 25(1): 49-58.e5, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30629918

RESUMO

Recent and ongoing outbreaks of Ebola virus disease (EVD) underscore the unpredictable nature of ebolavirus reemergence and the urgent need for antiviral treatments. Unfortunately, available experimental vaccines and immunotherapeutics are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against other ebolaviruses associated with EVD, including Sudan virus (SUDV) and Bundibugyo virus (BDBV). Here we show that MBP134AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs), affords unprecedented effectiveness and potency as a therapeutic countermeasure to antigenically diverse ebolaviruses. MBP134AF could fully protect ferrets against lethal EBOV, SUDV, and BDBV infection, and a single 25-mg/kg dose was sufficient to protect NHPs against all three viruses. The development of MBP134AF provides a successful model for the rapid discovery and translational advancement of immunotherapeutics targeting emerging infectious diseases.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Ebolavirus/patogenicidade , Furões/virologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Bem-Estar do Animal , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/administração & dosagem , Linhagem Celular , Cercopithecus aethiops , Modelos Animais de Doenças , Feminino , Filoviridae/imunologia , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/prevenção & controle , Infecções por Filoviridae/virologia , Glicoproteínas/imunologia , Cobaias , Células HEK293 , Doença pelo Vírus Ebola/virologia , Humanos , Células Matadoras Naturais , Macaca , Macaca fascicularis , Masculino , Primatas , Análise de Sobrevida , Resultado do Tratamento , Proteínas Virais/imunologia
11.
EBioMedicine ; 40: 574-582, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30638863

RESUMO

BACKGROUND: VIS410, a broadly neutralizing monoclonal antibody that binds the hemagglutinin stem of influenza A viruses, was safe and efficacious in a human H1N1 virus challenge study. This study evaluated the safety and tolerability of VIS410 in non-hospitalized adult patients with uncomplicated influenza A. METHODS: Patients 18 to 65 years of age with symptom onset within 72 h were randomized 1:1:1 to receive a single intravenous infusion of VIS410 4000 mg, 2000 mg, or placebo. Neuraminidase inhibitor therapy was prohibited. Treatment-emergent adverse events (TEAEs) were evaluated up to 100 days post-infusion. Influenza symptoms were assessed daily for 10 days using the FLU-PRO tool. Nasopharyngeal virus shedding was assessed by quantitative reverse-transcription PCR (qRT-PCR) and viral culture through Day 7. FINDINGS: Of the 150 patients randomized, 148 received study drug, and 138 were confirmed influenza A positive. Median age was 42 years; median time from symptom onset to treatment was 42 h; 93% had influenza A subtype H3N2. SAFETY: TEAEs, most commonly diarrhea of mild severity, were dose-related, occurring in 55%, 35%, and 24% of the 4000 mg, 2000 mg, and placebo patients, respectively. Two serious adverse events occurred, both in placebo patients. SYMPTOM ANALYSES: Baseline FLU-PRO symptom scores were balanced among groups. Mean scores were lower by Days 3 and 4 in the pooled VIS410 treatment group versus placebo (p < 0.023), with a tendency toward faster resolution by Kaplan-Meier analysis. VIROLOGY ANALYSES: VIS410 was associated with reduced median nasopharyngeal viral load TCID50 AUCDay7 (days × log10 TCID50/mL) (3.66 pooled VIS410 vs 4.78 placebo, p = 0.08) and in the subset of patients with baseline hemagglutination inhibition (HAI) titer ≤40 (overall, 74% of patients) was significantly reduced vs placebo (4.218 pooled VIS410 vs 6.152 placebo, p = 0.009). Kaplan-Meier estimated time to resolution of viral shedding was reduced (1.9 vs 3.6 days, p = 0.03) in VIS410 treated patients. There was a trend toward greater proportion of culture-negative patients by Day 3 (66.7% vs 51.1%, p = 0.11); when this analysis was limited to the subset of patients with positive baseline cultures, this difference became more pronounced (63.2% vs 42.5%, p = 0.053). No differences were observed in nasopharyngeal influenza qRT-PCR profiles, which represent both live and neutralized virus. INTERPRETATION: VIS410 was safe and well tolerated in adults with uncomplicated influenza A, with favorable effects on symptom resolution and virus replication. TRIAL REGISTRATION: Clinical Trials: NCT02989194. FUNDING: This project was funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201500018C.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antivirais/uso terapêutico , Vírus da Influenza A , Influenza Humana/tratamento farmacológico , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/uso terapêutico , Antivirais/administração & dosagem , Feminino , Humanos , Imunoterapia , Vírus da Influenza A/classificação , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Influenza Humana/diagnóstico , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Avaliação de Sintomas , Resultado do Tratamento , Carga Viral , Eliminação de Partículas Virais/efeitos dos fármacos
12.
Cell Host Microbe ; 25(1): 39-48.e5, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30629917

RESUMO

Passive administration of monoclonal antibodies (mAbs) is a promising therapeutic approach for Ebola virus disease (EVD). However, all mAbs and mAb cocktails that have entered clinical development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against outbreak-causing Bundibugyo virus (BDBV) and Sudan virus (SUDV). Here, we advance MBP134, a cocktail of two broadly neutralizing human mAbs, ADI-15878 from an EVD survivor and ADI-23774 from the same survivor but specificity-matured for SUDV GP binding affinity, as a candidate pan-ebolavirus therapeutic. MBP134 potently neutralized all ebolaviruses and demonstrated greater protective efficacy than ADI-15878 alone in EBOV-challenged guinea pigs. A second-generation cocktail, MBP134AF, engineered to effectively harness natural killer (NK) cells afforded additional improvement relative to its precursor in protective efficacy against EBOV and SUDV in guinea pigs. MBP134AF is an optimized mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Bem-Estar do Animal , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/uso terapêutico , Antivirais , Modelos Animais de Doenças , Ebolavirus/patogenicidade , Epitopos/imunologia , Feminino , Filoviridae/imunologia , Cobaias , Doença pelo Vírus Ebola/virologia , Humanos , Imunoterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Recombinantes/imunologia , Resultado do Tratamento
13.
Cell Host Microbe ; 25(1): 59-72.e8, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30629920

RESUMO

Eliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.


Assuntos
Anticorpos Neutralizantes/imunologia , Epitopos/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Vacinas , Sequência de Aminoácidos , Animais , Anticorpos Neutralizantes/uso terapêutico , Formação de Anticorpos , Modelos Animais de Doenças , Epitopos/genética , Feminino , Cobaias , Células HEK293 , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Imunização , Concentração Inibidora 50 , Modelos Moleculares , Mutação , Fragmentos de Peptídeos/imunologia , Ligação Proteica , Vacinação , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
14.
Cytokine Growth Factor Rev ; 45: 1-8, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30563755

RESUMO

Studies in recent years have identified a pivotal role of the cytokine IL-23 in the pathogenesis of inflammatory bowel diseases (IBD: Crohn´s disease, ulcerative colitis) and colitis-associated colon cancer. Genetic studies revealed that subgroups of IBD patients have single nucleotide polymorphisms in the IL-23R gene suggesting that IL-23R signaling affects disease susceptibility. Furthermore, increased production of IL-23 by macrophages, dendritic cells or granulocytes has been observed in various mouse models of colitis, colitis-associated cancer and IBD patients. Moreover, in several murine models of colitis, suppression of IL-12/IL-23 p40, IL-23 p19 or IL-23R function led to marked suppression of gut inflammation. This finding was associated with reduced activation of IL-23 target cells such as T helper 17 cells, innate lymphoid cells type 3, granulocytes and natural killer cells as well as with impaired production of proinflammatory cytokines. Based on these findings, targeting of IL-23 emerges as important concept for suppression of gut inflammation and inflammation-associated cancer growth. Consistently, neutralizing antibodies against IL-12/IL-23 p40 and IL-23 p19 have been successfully used in clinical trials for therapy of Crohn´s disease and pilot studies in ulcerative colitis are ongoing. These findings underline the crucial regulatory role of IL-23 in chronic intestinal inflammation and colitis-associated cancer and indicate that therapeutic strategies aiming at IL-23 blockade may be of key relevance for future therapy of IBD patients.


Assuntos
Neoplasias do Colo/imunologia , Imunidade Inata , Doenças Inflamatórias Intestinais/imunologia , Interleucina-23/imunologia , Animais , Anticorpos Neutralizantes/uso terapêutico , Ensaios Clínicos como Assunto , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Doença de Crohn/terapia , Citocinas/imunologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Camundongos , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Células Th17/imunologia
15.
Int Immunopharmacol ; 67: 386-395, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30584968

RESUMO

Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome with uncontrolled inflammation that is a central issue. Its main characteristic is inflammatory mediators and cytokines as well as agglutinating chemokines that injure target cells. Interleukin (IL)-35 is a newly identified IL-12 cytokine family member with structural similarities to other IL-12, IL-23, and IL-27 cytokines but unique immunological functions. How IL-35 functions in ARDS is unclear. The purpose of our study was to determine what role IL-35 played in the development of ARDS. Here we found serum IL-35 concentrations were significantly elevated in patients with ARDS relative to healthy people. Moreover, we established a mouse model of lipopolysaccharide- and cecal ligation and puncture-induced ARDS treated with neutralizing antibodies (anti-IL-35 Ebi3 or anti-IL-35 P35); the results showed that lung injury occurred more often than in untreated models and the inflammatory cytokines CXCL-1, tumor necrosis factor alpha, IL-6, and IL-17A increased significantly after neutralizing antibody treatment in bronchoalveolar lavage fluid and serum. Therefore IL-35 can protect against the development of ARDS. Even more interesting in our study was that we discovered IL-35 expression differed between lung and spleen across different ARDS models, which further demonstrated that the spleen likely has an important role in extrapulmonary ARDS model only, improving the ratio of CD4+/CD4+CD25+Foxp3+(Tregs). Meanwhile in our clinical work, we also found that the concentration of IL-35 and the ratio of CD4+/Treg in the serum are higher and the mortality is lower than those with the spleen deficiency in patients with extrapulmonary ARDS. Therefore, IL-35 is protective in ARDS by promoting the ratio of splenic CD4+/Tregs in extrapulmonary ARDS, and as such, may be a therapeutic target.


Assuntos
Interleucinas/sangue , Interleucinas/metabolismo , Síndrome do Desconforto Respiratório do Adulto/imunologia , Linfócitos T/fisiologia , Idoso , Animais , Anticorpos Neutralizantes/uso terapêutico , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/toxicidade , Pulmão , Masculino , Camundongos , Pessoa de Meia-Idade , Baço , Linfócitos T/classificação
16.
Methods Mol Biol ; 1911: 481-503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30593647

RESUMO

In spite of the immense progress in hepatitis C virus (HCV) research, efforts to prevent infection, such as generating a vaccine, have not yet been successful. The high price tag associated with current treatment options for chronic infection and the spike in new infections concurrent with growing opioid abuse are strong motivators for developing effective immunization and understanding neutralizing antibodies' role in preventing infection. Humanized mice-both human liver chimeras as well as genetically humanized models-are important platforms for testing both possible vaccine candidates as well as antibody-based therapies. This chapter details the variety of ways humanized mouse technology can be employed in pursuit of learning how HCV infection can be prevented.


Assuntos
Anticorpos Neutralizantes/imunologia , Modelos Animais de Doenças , Hepacivirus/imunologia , Hepatite C/prevenção & controle , Vacinas contra Hepatite Viral/imunologia , Animais , Anticorpos Neutralizantes/uso terapêutico , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Imunogenicidade da Vacina , Fígado/citologia , Fígado/imunologia , Transplante de Fígado , Camundongos , Camundongos Transgênicos , Testes de Neutralização/instrumentação , Testes de Neutralização/métodos , Quimeras de Transplante , Resultado do Tratamento , Proteínas do Envelope Viral/imunologia , Vacinas contra Hepatite Viral/uso terapêutico
17.
Int J Mol Sci ; 20(1)2018 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-30587780

RESUMO

Osteoporosis represents the most common bone disease worldwide and results in a significantly increased fracture risk. Extrinsic and intrinsic factors implicated in the development of osteoporosis are also associated with delayed fracture healing and impaired bone regeneration. Based on a steadily increasing life expectancy in modern societies, the global implications of osteoporosis and impaired bone healing are substantial. Research in the last decades has revealed several molecular pathways that stimulate bone formation and could be targeted to treat both osteoporosis and impaired fracture healing. The identification and development of therapeutic approaches modulating bone formation, rather than bone resorption, fulfils an essential clinical need, as treatment options for reversing bone loss and promoting bone regeneration are limited. This review focuses on currently available and future approaches that may have the potential to achieve these aims.


Assuntos
Anabolizantes/uso terapêutico , Regeneração Óssea/fisiologia , Osteoporose/tratamento farmacológico , Anticorpos Neutralizantes/uso terapêutico , Proteínas Morfogenéticas Ósseas/imunologia , Proteínas Morfogenéticas Ósseas/metabolismo , Fraturas Ósseas/tratamento farmacológico , Humanos , Osteoporose/metabolismo , Osteoporose/patologia , Hormônio Paratireóideo/uso terapêutico , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Via de Sinalização Wnt
18.
BMC Infect Dis ; 18(1): 641, 2018 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-30526531

RESUMO

BACKGROUND: Dengue Virus (DENV) and Zika Virus (ZIKV) are closely related flaviviruses, circulating in overlapping geographical regions. The recent ZIKV epidemic has been linked to an explosion in reports of microcephaly and neurological defects. It is conceivable that our knowledge of DENV might potentiate the development of a ZIKV vaccine due to the close phylogenetic relationship between these flaviviruses and cross-reactive antibodies, principally to the envelope protein (E protein). Alternatively, cross-reactive antibodies that are generated following vaccination or infection, might become damaging during subsequent infections. MAIN BODY: The aims of this review are to collate and analyse data from a recent series of DENV-derived monoclonal antibody (mAb) panels from different research groups. These panels measured DENV-mAb activity against ZIKV in terms of antibody-dependent enhancement (ADE) and neutralisation. Methodology used across groups was compared and critiqued. Furthermore, the specific antibody targets on E protein were considered and their therapeutic potential evaluated. Shortcomings of hmAb panels suggest ADE may be over-estimated and neutralisation underestimated, as compared to clinical situations. It remains unknown whether preference of enhancement or neutralisation by antibodies to ZIKV E protein is dictated by quantitative aspects of antibody titre or epitope specific variation. Additionally, little is known about how duration between flavivirus reinfections affect secondary antibody response. CONCLUSION: This review concludes that our current knowledge of cross-reactive antibodies to E protein is inadequate to anticipate the outcome of deploying an E protein based vaccine to regions co-infected by DENV and ZIKV.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Vírus da Dengue/imunologia , Dengue/prevenção & controle , Proteínas do Envelope Viral/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Facilitadores/fisiologia , Reações Cruzadas/imunologia , Dengue/epidemiologia , Vírus da Dengue/patogenicidade , Humanos , Zika virus/patogenicidade , Infecção por Zika virus/epidemiologia
19.
Transfusion ; 58 Suppl 3: 3096-3105, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30536430

RESUMO

Immune-deficient patients depend on the antibodies in pooled human immunoglobulin G (IgG) preparations to remain free from serious infections. The potency of IgG preparations is therefore an ongoing concern. The use of pooled IgG to prevent infection is based on the concept that healthy adults have recovered from infections earlier in life and maintain relatively high antibody titers. In general, vaccine-induced immunity is less robust or long-lasting than immunity after natural infection, and many infectious diseases which were formerly widely prevalent have become much less common due to improved hygiene and vaccines. This raises questions as to the adequacy of protective antibodies in current IgG preparations. This paper reviews available data on antibodies against selected bacterial and virus vaccine antigens in current IgG products. Most products contain sufficient antibody to yield levels above minimal protective concentrations to a broad range of pathogens and toxins. Illustrative examples of effects of vaccines on antibody content of IgG products are also discussed: antibody titers to hepatitis A virus in donor plasma pools in both the US and EU are dropping due to decreased natural infection, but they are still sufficient to provide robust protection. Increasing seroprevalence of hepatitis B virus as a result of immunization suggests that antibody titers against this virus may actually be increasing. Finally, serial studies suggest that pooled IgG provides protection against seasonal influenza viruses despite year-to-year antigenic drift, and is also likely to provide at least some protective antibody against potentially pandemic strains.


Assuntos
Anticorpos Antivirais/análise , Imunoglobulina G/administração & dosagem , Imunoglobulina G/imunologia , Vacinas Virais/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/sangue , Anticorpos Antivirais/uso terapêutico , Bactérias/imunologia , Toxinas Bacterianas/imunologia , Combinação de Medicamentos , Humanos , Imunoglobulina G/uso terapêutico , Ligação Proteica , Vacinação/métodos
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