RESUMO
BACKGROUND: The effect of pneumococcal vaccination of mothers with human immunodeficiency virus (HIV) on infant responses to childhood vaccination has not been studied. We compared the immunogenicity of 10-valent pneumococcus conjugate vaccine (PCV-10) in HIV-exposed uninfected infants born to mothers who received PCV-10, 23-valent pneumococcus polysaccharide vaccine (PPV-23), or placebo during pregnancy. METHODS: Antibody levels against 7 serotypes were measured at birth, before the first and second doses of PCV-10m and after completion of the 2-dose regimen in 347 infants, including 112 born to mothers who received PPV-23, 112 who received PCV-10, and 119 who received placebo during pregnancy. Seroprotection was defined by antibody levels ≥0.35 µg/mL. RESULTS: At birth and at 8 weeks of life, antibody levels were similar in infants born to PCV-10 or PPV-23 recipients and higher than in those born to placebo recipient. After the last dose of PCV-10, infants in the maternal PCV-10 group had significantly lower antibody levels against 5 serotypes than those in the maternal PPV-23 group and against 3 serotypes than those in the maternal placebo group, and they did not have higher antibody levels against any serotype. The seroprotection rate against 7 serotypes was 50% in infants in the maternal PCV-10 group, compared with 71% in both of the maternal PPV-23 and placebo groups (Pâ <â .001). CONCLUSIONS: Administration of PCV-10 during pregnancy was associated with decreased antibody responses to PCV-10 and seroprotection rates in infants. Considering that PCV-10 and PPV-23 had similar immunogenicity in pregnant women with HIV and that administration of PPV-23 did not affect the immunogenicity of PCV-10 in infants, PPV-23 in pregnancy may be preferred over PCV-10.
Assuntos
Infecções por HIV , Infecções Pneumocócicas , Anticorpos Antibacterianos/uso terapêutico , Feminino , HIV , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Polissacarídeos , Gravidez , Streptococcus pneumoniae , Vacinação , Vacinas ConjugadasRESUMO
Passive immunization with antibodies is a promising approach against enterotoxigenic Escherichia coli diarrhea, a prevalent disease in LMICs. The objective of this study was to investigate expression of a monoclonal anti-ETEC CfaE secretory IgA antibody in N. benthamiana plants, with a view to facilitating access to ETEC passive immunotherapy. SIgA1 and SIgA2 forms of mAb 68-81 were produced by co-expressing the light and engineered heavy chains with J chain and secretory component in N. benthamiana. Antibody expression and assembly were compared with CHO-derived antibodies by SDS-PAGE, western blotting, size-exclusion chromatography and LC-MS peptide mapping. N-linked glycosylation was assessed by rapid fluorescence/mass spectrometry and LC-ESI-MS. Susceptibility to gastric digestion was assessed in an in vitro model. Antibody function was compared for antigen binding, a Caco-2 cell-based ETEC adhesion assay, an ETEC hemagglutination inhibition assay and a murine in vivo challenge study. SIgA1 assembly appeared superior to SIgA2 in plants. Both sub-classes exhibited resistance to degradation by simulated gastric fluid, comparable to CHO-produced 68-61 SIgA1. The plant expressed SIgAs had more homogeneous N-glycosylation than CHO-derived SIgAs, but no alteration of in vitro functional activity was observed, including antibodies expressed in a plant line engineered for mammalian-like N glycosylation. The plant-derived SIgA2 mAb demonstrated protection against diarrhea in a murine infection model. Although antibody yield and purification need to be optimized, anti-ETEC SIgA antibodies produced in a low-cost plant platform are functionally equivalent to CHO antibodies, and provide promise for passive immunotherapy in LMICs.
Assuntos
Anticorpos Monoclonais/imunologia , Escherichia coli Enterotoxigênica/imunologia , Imunoglobulina A Secretora/imunologia , Nicotiana/metabolismo , Animais , Anticorpos Antibacterianos/genética , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/metabolismo , Anticorpos Antibacterianos/uso terapêutico , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Afinidade de Anticorpos , Aderência Bacteriana/efeitos dos fármacos , Células CACO-2 , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/terapia , Ácido Gástrico/metabolismo , Glicosilação , Humanos , Imunoglobulina A Secretora/genética , Imunoglobulina A Secretora/metabolismo , Imunoglobulina A Secretora/uso terapêutico , Imunoterapia , Camundongos , Plantas Geneticamente Modificadas , Nicotiana/genéticaRESUMO
PURPOSE: The hypoxic microenvironments of solid tumours are complex and reduce the susceptibility of cancer cells to chemo- and radiotherapy. Conventional radiosensitisers have poor specificity, unsatisfactory therapeutic effects, and significant side effects. Anaerobic bacteria colonise and destroy hypoxic areas of the tumour and consequently enhance the effects of radiation. METHODS: In this study, we treated a Lewis lung carcinoma transplant mouse model with Bifidobacterium infantis (Bi) combined with its specific monoclonal antibody (mAb) and radiotherapy (RT) to investigate its ability to radiosensitise the tumour. The tumour metabolism and hypoxia in the tumour tissue were monitored by micro-18F-FDG and 18F-FMISO PET/CT imaging. Immunohistochemistry was used to detect phosphorylated histone (γ-H2AX), proliferation (Ki-67), platelet endothelial cell adhesion molecules (CD31), tumour necrosis factor-α (TNF-α), hypoxia-inducible factor-1α (HIF-1α), and glucose transporter 1 (Glut-1) levels. RESULTS: Tumour growth was slowed and survival time was markedly prolonged in mice subjected to the combination of B. infantis, specific antibody, and radiotherapy. Levels of HIF-1α, Glut-1, Ki-67, and CD31 expression, as well as uptake of FDG and FMISO, were the lowest in the combination-treated mice. In contrast, γ-H2AX and TNF-α expression levels were elevated and hypoxia in tumour tissue was reduced compared with controls. CONCLUSION: In conclusion, our data indicated that the curative effect of radiotherapy for lung cancer was enhanced by pre-treating mice with a combination of B. infantis and its specific monoclonal antibody.
Assuntos
Anticorpos Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Bifidobacterium longum subspecies infantis , Carcinoma Pulmonar de Lewis/radioterapia , Radiossensibilizantes/uso terapêutico , Animais , Bifidobacterium longum subspecies infantis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/mortalidade , Carcinoma Pulmonar de Lewis/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Glucose/metabolismo , Histonas/análise , Antígeno Ki-67/análise , Camundongos , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
Francisella tularensis (Ft), the causative agent of lethal tularemia, is classified as a category A biological warfare threat agent. While Ft infection is treatable by antibiotics, many failed antibiotic treatments were reported, highlighting the need for effective new treatments. It has been demonstrated that binding of antibody-coated bacteria to the Fc receptor located on phagocytic cells is a key process needed for efficient protection against Ft. Yet, Ft utilizes the same receptor to enter the phagocytic cells in order to escape the immune system. To address the question whether an anti-Ft LPS antibody lacking the ability to bind the Fc receptor may inhibit the entry of Ft into host cells, a soluble scFv (TL1-scFv) was constructed from an anti Ft-LPS antibody (TL1) that was isolated from an immune single-chain (scFv) phage-display library. Bacterial uptake was assessed upon infection of macrophages with Ft live attenuated strain (LVS) in the presence of either TL1 or TL1-scFv. While incubation of LVS in the presence of TL1 greatly enhanced bacterial uptake, LVS uptake was significantly inhibited in the presence of TL1-scFv. These results prompt further experiments probing the therapeutic efficacy of TL1-scFv, alone or in combination with antibiotic treatment.
Assuntos
Anticorpos Antibacterianos/farmacologia , Francisella tularensis/imunologia , Lipopolissacarídeos/imunologia , Fagocitose/efeitos dos fármacos , Anticorpos de Cadeia Única/farmacologia , Tularemia/tratamento farmacológico , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/isolamento & purificação , Anticorpos Antibacterianos/uso terapêutico , Vacinas Bacterianas/administração & dosagem , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Fagocitose/imunologia , Coelhos , Anticorpos de Cadeia Única/sangue , Anticorpos de Cadeia Única/isolamento & purificação , Anticorpos de Cadeia Única/uso terapêutico , Tularemia/sangue , Tularemia/imunologia , Tularemia/microbiologia , Vacinas Atenuadas/administração & dosagemRESUMO
The ultimate goal of this research was to overcome the low immunogenicity of the biological macromolecule (heat stable enterotoxin STa) via its conjugation to biodegradable PLGA nanoparticles (NP). STa was first isolated from Enterotoxigenic Escherichia coli (ETEC), purified and identified using reported HPLC procedures. Optimized homogenous PLGA NP, prepared using the nanoprecipitation technique were used for conjugating STa using the carbodiimide synthesis. Covalent binding of STa to PLGA NP was confirmed via FTIR and 1HNMR analysis. Safety and tolerability of the developed nanoparticulated STa-PLGA conjugate were confirmed by MTT assay on A549 lung cancer cells. After subcutaneous immunization, STA-PLGA NP conjugate induced a significant immune response in mice showing a strong binding and neutralizing antibody titer. The developed novel STa-PLGA NP conjugate is expected to provide promising protection against enterotoxigenic Escherichia coli (ETEC).
Assuntos
Toxinas Bacterianas/química , Escherichia coli Enterotoxigênica/química , Enterotoxinas/química , Infecções por Escherichia coli/prevenção & controle , Proteínas de Escherichia coli/química , Imunização , Animais , Anticorpos Antibacterianos/química , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/uso terapêutico , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Toxinas Bacterianas/imunologia , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/uso terapêutico , Escherichia coli Enterotoxigênica/imunologia , Enterotoxinas/imunologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/imunologia , Humanos , Ácido Láctico/química , Ácido Láctico/uso terapêutico , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Ácido Poliglicólico/química , Ácido Poliglicólico/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
Streptococcus pneumoniae is the main cause of bacterial meningitis, a life-threating disease with a high case fatality rate despite treatment with antibiotics. Pneumococci cause meningitis by invading the blood and penetrating the blood-brain barrier (BBB). Using stimulated emission depletion (STED) super-resolution microscopy of brain biopsies from patients who died of pneumococcal meningitis, we observe that pneumococci colocalize with the two BBB endothelial receptors: polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1). We show that the major adhesin of the pneumococcal pilus-1, RrgA, binds both receptors, whereas the choline binding protein PspC binds, but to a lower extent, only pIgR. Using a bacteremia-derived meningitis model and mutant mice, as well as antibodies against the two receptors, we prevent pneumococcal entry into the brain and meningitis development. By adding antibodies to antibiotic (ceftriaxone)-treated mice, we further reduce the bacterial burden in the brain. Our data suggest that inhibition of pIgR and PECAM-1 has the potential to prevent pneumococcal meningitis.
Assuntos
Adesinas Bacterianas/metabolismo , Proteínas de Bactérias/metabolismo , Encéfalo/microbiologia , Proteínas de Fímbrias/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Imunoglobulina Polimérica/metabolismo , Streptococcus pneumoniae/patogenicidade , Fatores de Virulência/metabolismo , Animais , Anticorpos Antibacterianos/farmacologia , Anticorpos Antibacterianos/uso terapêutico , Biópsia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/microbiologia , Barreira Hematoencefálica/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/microbiologia , Humanos , Meningites Bacterianas/tratamento farmacológico , Meningites Bacterianas/microbiologia , Meningites Bacterianas/patologia , Camundongos Endogâmicos C57BL , Microscopia , Ligação Proteica/efeitos dos fármacos , Streptococcus pneumoniae/isolamento & purificaçãoRESUMO
Hypervirulent Klebsiella pneumoniae (hvKp) strains are predicted to become a major threat in Asia if antibiotic resistance continues to spread. Anticapsular antibodies (Abs) were developed because disseminated infections caused by hvKp are associated with significant morbidity and mortality, even with antibiotic-sensitive strains. K1-serotype polysaccharide capsules (K1-CPS) are expressed by the majority of hvKp strains. In this study, K1-CPS-specific IgG Abs were generated by conjugation of K1-CPS to immunogenic anthrax protective antigen (PA) protein. Opsonophagocytic efficacy was measured in vitro and in vivo by intravital microscopy in murine livers. In vivo protection was tested in murine models, including a novel model for dissemination in hvKp-colonized mice. Protective efficacy of monoclonal antibodies (MAbs) 4C5 (IgG1) and 19A10 (IgG3) was demonstrated both in murine sepsis and pulmonary infection. In hvKp-colonized mice, MAb treatment significantly decreased dissemination of hvKp from the gut to mesenteric lymph nodes and organs. Intravital microscopy confirmed efficient opsonophagocytosis and clearance of bacteria from the liver. In vitro studies demonstrate that MAbs work predominantly by promoting FcR-mediated phagocytosis but also indicate that MAbs enhance the release of neutrophil extracellular traps (NETs). In anticipation of increasing antibiotic resistance, we propose further development of these and other Klebsiella-specific MAbs for therapeutic use.
Assuntos
Anticorpos Antibacterianos/uso terapêutico , Quimioprevenção/métodos , Imunoterapia/métodos , Infecções por Klebsiella/prevenção & controle , Infecções por Klebsiella/terapia , Klebsiella pneumoniae/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Cápsulas Bacterianas/imunologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose , Pneumonia Bacteriana/prevenção & controle , Pneumonia Bacteriana/terapia , Sepse/prevenção & controle , Sepse/terapia , Resultado do TratamentoRESUMO
Clostridium difficile infection (CDI), a leading cause of nosocomial infection, is a serious disease in North America, Europe, and Asia. CDI varies greatly from asymptomatic carriage to life-threatening diarrhea, toxic megacolon, and toxemia. The incidence of community-acquired infection has increased due to the emergence of hypervirulent antibiotic-resistant strains. These new strains contribute to the frequent occurrence of disease relapse, complicating treatment, increasing hospital stays, and increasing morbidity and mortality among patients. Therefore, it is critical to develop new therapeutic approaches that bypass the development of antimicrobial resistance and avoid disruption of gut microflora. Here, we describe the construction of a single heteromultimeric VHH-based neutralizing agent (VNA) that targets the two primary virulence factors of Clostridium difficile, toxins A (TcdA) and B (TcdB). Designated VNA2-Tcd, this agent has subnanomolar toxin neutralization potencies for both C. difficile toxins in cell assays. When given systemically by parenteral administration, VNA2-Tcd protected against CDI in gnotobiotic piglets and mice and to a lesser extent in hamsters. Protection from CDI was also observed in gnotobiotic piglets treated by gene therapy with an adenovirus that promoted the expression of VNA2-Tcd.
Assuntos
Anticorpos Antibacterianos/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antitoxinas/uso terapêutico , Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/microbiologia , Infecções por Clostridium/terapia , Adenoviridae/genética , Animais , Proteínas de Bactérias/antagonistas & inibidores , Toxinas Bacterianas/antagonistas & inibidores , Modelos Animais de Doenças , Portadores de Fármacos , Avaliação Pré-Clínica de Medicamentos , Enterotoxinas/antagonistas & inibidores , Terapia Genética/métodos , Mesocricetus , Camundongos Endogâmicos C57BL , Suínos , Resultado do TratamentoRESUMO
BACKGROUND: Oral prophylactic therapy by gargling with pathogen-specific egg yolk immunoglobulins (IgY) may reduce the initial airway colonization with Pseudomonas aeruginosa in cystic fibrosis (CF) patients. IgY antibodies impart passive immunization and we investigated the effects of anti-P. aeruginosa IgY antibodies on bacterial eradication in a murine pneumonia model. METHODS: P. aeruginosa pneumonia was established in Balb/c mice and the effects of prophylactic IgY administration on lung bacteriology, clinical parameters and subsequent inflammation were compared to controls. RESULTS: Prophylactic administration of IgY antibodies targeting P. aeruginosa significantly reduced the bacterial burden by 2-log 24h post-infection compared to controls and was accompanied by significantly reduced clinical symptom scores and successive inflammatory cytokine profile indicative of diminished lung inflammation. CONCLUSIONS: Passive immunization by anti-P. aeruginosa IgY therapy facilitates promptly bacterial clearance and moderates inflammation in P. aeruginosa lung infection and may serve as an adjunct to antibiotics in reducing early colonization.
Assuntos
Anticorpos Anti-Idiotípicos/uso terapêutico , Anticorpos Antibacterianos/uso terapêutico , Imunoglobulinas/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/imunologia , Doença Aguda , Animais , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Antibacterianos/imunologia , Modelos Animais de Doenças , Feminino , Imunoglobulinas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Viabilidade Microbiana , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificaçãoRESUMO
Acinetobacter baumannii (A. baumannii) is an important conditioned pathogen that causes nosocomial and community-associated infections. In this study, we sought to investigate whether outer membrane protein W (OmpW) is a potential target for eliciting protective immunity against A. baumannii infections. Mice immunized with the fusion protein thioredoxin-OmpW generated strong OmpW-specific IgG responses. In a sepsis model, both active and passive immunizations against OmpW effectively protected mice from A. baumannii infections. This protection was demonstrated by a significantly improved survival rate, reduced bacterial burdens within organs, and the suppressed accumulation of inflammatory cytokines and chemokines in sera. Opsonophagocytic assays with murine macrophage RAW264.7 cells indicated that the bactericidal effects of the antisera derived from the immunized mice are mediated synergistically by specific antibodies and complement components. The antisera presented significant opsonophagocytic activities against homologous strains and clonally distinct clinical isolates in vitro. Protein data analysis showed that the sequence of OmpW, which has a molecule length of 183 amino acids, is more than 91% conserved in reported A. baumannii strains. In conclusion, we identified OmpW as a highly immunogenic and conserved protein as a valuable antigen candidate for the development of an effective vaccine or the preparation of antisera to control A. baumannii infections.
Assuntos
Infecções por Acinetobacter/prevenção & controle , Acinetobacter baumannii/imunologia , Anticorpos Antibacterianos/uso terapêutico , Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/imunologia , Sepse/prevenção & controle , Infecções por Acinetobacter/imunologia , Acinetobacter baumannii/genética , Estruturas Animais/microbiologia , Animais , Anticorpos Antibacterianos/sangue , Carga Bacteriana , Proteínas da Membrana Bacteriana Externa/genética , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Proteínas do Sistema Complemento/imunologia , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Imunização Passiva , Imunoglobulina G/sangue , Imunoglobulina G/uso terapêutico , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos ICR , Proteínas Opsonizantes/sangue , Células RAW 264.7 , Sepse/imunologia , Análise de Sobrevida , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
Widespread drug resistance due to empiric use of broad-spectrum antibiotics has stimulated development of bacteria-specific strategies for prophylaxis and therapy based on modern monoclonal antibody (mAb) technologies. However, single-mechanism mAb approaches have not provided adequate protective activity in the clinic. We constructed multifunctional bispecific antibodies, each conferring three mechanisms of action against the bacterial pathogen Pseudomonas aeruginosa by targeting the serotype-independent type III secretion system (injectisome) virulence factor PcrV and persistence factor Psl exopolysaccharide. A new bispecific antibody platform, BiS4, exhibited superior synergistic protection against P. aeruginosa-induced murine pneumonia compared to parent mAb combinations or other available bispecific antibody structures. BiS4αPa was protective in several mouse infection models against disparate P. aeruginosa strains and unexpectedly further synergized with multiple antibiotic classes even against drug-resistant clinical isolates. In addition to resulting in a multimechanistic clinical candidate (MEDI3902) for the prevention or treatment of P. aeruginosa infections, these antibody studies suggest that multifunctional antibody approaches may be a promising platform for targeting other antibiotic-resistant bacterial pathogens.
Assuntos
Anticorpos Antibacterianos/uso terapêutico , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Infecções por Pseudomonas/terapia , Pseudomonas aeruginosa/imunologia , Animais , Antibacterianos/farmacologia , Anticorpos Antibacterianos/química , Anticorpos Biespecíficos/química , Anticorpos Monoclonais/química , Antígenos de Bactérias/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Farmacorresistência Bacteriana , Humanos , Camundongos , Conformação Molecular , Fagocitose , Infecções por Pseudomonas/imunologiaRESUMO
Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality in cystic fibrosis (CF). The type III secretion system is one of the factors responsible for the increased virulence and pro-inflammatory effects of Pa. KB001 is a PEGylated, recombinant, anti-Pseudomonas-PcrV antibody Fab' fragment that blocks the function of Pa TTSS. We studied the safety, pharmacokinetic (PK), and pharmacodynamic properties of KB001 in CF subjects with chronic Pa infection. Twenty-seven eligible CF subjects (≥12 years of age, FEV1 ≥40% of predicted, and sputum Pa density >10(5) CFU/g) received a single intravenous dose of KB001 (3 mg/kg or 10 mg/kg) or placebo. Safety, PK, Pa density, clinical outcomes, and inflammatory markers were assessed. KB001 had an acceptable safety profile and a mean serum half-life of 11.9 days. All subjects had Pa TTSS expression in sputum. There were no significant differences between KB001 and placebo for changes in Pa density, symptoms, or spirometry after a single dose. However, compared to baseline, at Day 28 there was a trend towards a dose-dependent reduction in sputum myeloperoxidase, IL-1, and IL-8, and there were significant overall differences in change in sputum neutrophil elastase and neutrophil counts favoring the KB001 10 mg/kg group versus placebo (-0.61 log(10) and -0.63 log(10) , respectively; P < 0.05). These results support targeting Pa TTSS with KB001 as a nonantibiotic strategy to reduce airway inflammation and damage in CF patients with chronic Pa infection. Repeat-dosing studies are necessary to evaluate the durability of the anti-inflammatory effects and how that may translate into clinical benefit. (NCT00638365).
Assuntos
Antibacterianos/uso terapêutico , Anticorpos Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Fibrose Cística/complicações , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , Adulto , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Anticorpos Antibacterianos/farmacologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Biomarcadores/metabolismo , Doença Crônica , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Meia-Vida , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Injeções Intravenosas , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Infecções por Pseudomonas/etiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/metabolismo , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Infecções Respiratórias/etiologia , Infecções Respiratórias/microbiologia , Escarro/metabolismo , Escarro/microbiologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: It is known that idiopathic chronic urticaria occasionally develops with Helicobacter pylori (H. pylori) infection, but the association between urticaria and H. pylori remains unknown. METHODS: We focused on the relationship between the titer of anti H. pylori IgG antibodies and urticaria. Sixty-five patients with idiopathic urticaria were divided into 3 groups by a difference of their titers. All patients in the high titer (≥40U/ml) group underwent endoscopy of the upper gastrointestinal tract with antral biopsy for the Rapid Urease Test (RUT) or a culture test. We investigated the relationship between the efficacy of eradication therapy against H. pylori and urticaria. RESULTS: The positive rate for H. pylori was 100% (20/20) by RUT or culture test in the high titer group. A CR using antihistamines alone was 0% (0/20) in the high titer group, 27.2% (3/11) in the low titer group and 38.2% (13/34) in the negative group respectively. A CR or PR using antihistamines was 70% (14/20) in the high titer group, 81.8% (9/11) in the low titer group and 97.1% (33/34) in the negative group. After successful eradication therapy, the CR was increased to 56% (9/16) in the high titer group. CONCLUSIONS: Regardless of acute or chronic urticaria, a high titer of anti H. pylori IgG antibody can be an indicator for undergoing upper endoscopy, and eradication therapy is strongly recommended. It will be necessary to develop diagnostic criteria for urticaria associated with H. pylori.
Assuntos
Anticorpos Antibacterianos/uso terapêutico , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Imunoglobulina G/uso terapêutico , Urticária/tratamento farmacológico , Urticária/imunologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Feminino , Infecções por Helicobacter/complicações , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Urticária/complicaçõesRESUMO
This study assessed the diagnostic approaches of Helicobacter pylori (IP)-associated iron deficiency (ID) and anemia (IDA) in children with dyspeptic symptoms and evaluated the effect of simultaneous anti-H. pylori (anti-HIP) therapy and oral iron in comparison with each of anti? HP therapy and oral iron therapy alone, on iron status as assessed by serum soluble transferrin receptor (sTfR) level. Two hundreds children with dyspeptic symptoms were subjected to clinical evaluation, stool examination, CBC, biochemical assays for serum iron parameters and measurements of serum IgG antibodies to HP and serum sTfR level by ELISA. Sixty children were found to have HP. associated ID or IDA and were randomly divided into 3 groups (20 children each). GA received 2-week anti-HP therapy plus 90-day oral iron, and GB received 2-week anti-HP therapy alone whereas group C received 90-day oral iron alone. Re-evaluation of the 3 groups was performed after 3 months of treatment initiation by repeat CBC and serum sTfR level. Children (45%) were HP-seropositive. The mean values of serum sTfR were significantly higher in HP-positive group and in HP-positive children with IDA than in HP-negative group and in HP-negative children with IDA although no significant differences were noted in hematologic variables and iron parameters between the corresponding groups and children. As regard treatment groups, there were significant improvements in the mean values of indices of IDA status (HIb, MCH, MCV, sTfR) and ID status (sTtRi) at 3 months of treatment initiation compared with their baseline values after. anti-HP triple therapy either with oral iron or without oral iron whereas the control children who were treated with oral iron alone showed insignificant changes despite oral iron administration. The improvements in these parameters were significantly greater in groups of children who received anti-HP therapy either combined with iron or alone, where compared with those who did not receive anti-HP therapy. Their magnitudes were significantly higher among children receiving anti-HP therapy combined with oral iron when compared with that receiving anti-HP therapy alone.
Assuntos
Anemia Ferropriva/etiologia , Dispepsia/etiologia , Infecções por Helicobacter/complicações , Helicobacter pylori , Adolescente , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/tratamento farmacológico , Antibacterianos/uso terapêutico , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/uso terapêutico , Biomarcadores , Criança , Pré-Escolar , Dispepsia/tratamento farmacológico , Dispepsia/microbiologia , Feminino , Ferritinas/sangue , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/imunologia , Humanos , Imunoglobulina G/sangue , Ferro/sangue , Ferro/uso terapêutico , Masculino , Receptores da Transferrina/sangueRESUMO
Novel approaches to the treatment of infectious diseases are urgently needed. This need has resulted in renewing the interest in antibodies for therapy of infectious diseases. Radioimmunotherapy (RIT) is a cancer treatment modality that utilizes radiolabeled monoclonal antibodies. During the last decade we have translated RIT into the field of experimental fungal, bacterial, and HIV infections. In addition, successful proof of principle experiments with radiolabeled pan-antibodies that bind to antigens shared by major pathogenic fungi have been performed in vitro. The armamentarium of pan-antibodies would result in reducing our dependence on microorganism-specific antibodies and thus would speed up the development of RIT for infections. We believe that the time is ripe for deploying RIT in the clinic to combat infectious diseases.
Assuntos
Anticorpos Antibacterianos/uso terapêutico , Anticorpos Antifúngicos/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Doenças Transmissíveis/terapia , Radioimunoterapia/métodos , Animais , Anticorpos Antibacterianos/química , Anticorpos Antibacterianos/imunologia , Anticorpos Antifúngicos/química , Anticorpos Antifúngicos/imunologia , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , HumanosRESUMO
Adhesins need to be exposed on the surface of pathogenic bacteria to properly interact with host tissues and allow establishment of the infection. This fact implies that, in theory, one could manage or avoid infection by controlling adhesins' function, and also by indirectly detecting bacteria through their surface-exposed adhesins. Besides, binding of anti-adhesin immunoglobulins on the bacterial surface tend to promote the opsonization of the pathogen. Therefore, bacterial adhesins represent a great target to develop new biopharmaceuticals, which may become commercially and medically important products. In this review, we will summarize the biological importance of bacterial adhesins, and also discuss some recent patents related to these molecules, as well as their use and possible new future developments in this area.
Assuntos
Adesinas Bacterianas/metabolismo , Anticorpos Antibacterianos/uso terapêutico , Bactérias/imunologia , Infecções Bacterianas/diagnóstico , Patentes como Assunto , Adesinas Bacterianas/genética , Animais , Bactérias/metabolismo , Aderência Bacteriana/efeitos dos fármacos , Infecções Bacterianas/terapia , Vacinas Bacterianas/uso terapêutico , Fímbrias Bacterianas/efeitos dos fármacos , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Camundongos , Neoplasias/diagnóstico , Bibliotecas de Moléculas Pequenas/uso terapêuticoRESUMO
Abs confer protection from secondary infection with Legionella pneumophila, the causative agent of a severe form of pneumonia known as Legionnaires' disease. In this study, we demonstrate that Ab-mediated protection is effective across L. pneumophila serogroups, suggesting that Abs specific for conserved protein Ags are sufficient to mediate this protective effect. We used two independent methods to identify immunogenic L. pneumophila protein Ags, namely, the screening of a λ phage library representing the complete L. pneumophila genome and two-dimensional gel electrophoresis combined with Western blot analysis and protein spot identification by mass spectrometry. A total of 30 novel L. pneumophila B cell Ags were identified, the majority of which are located in or associated with the bacterial membrane, where they are accessible for Abs and, therefore, likely to be relevant for Ab-mediated protection against L. pneumophila. Selected B cell Ags were recombinantly expressed and tested in a vaccination protocol. Mice immunized with either single-protein Ags or an Ag combination showed reduced bacterial titers in bronchoalveolar lavage and lung after L. pneumophila challenge. To determine the clinical relevance of these findings, we tested Legionnaires' disease patient sera for reactivity with the identified L. pneumophila Ags. The recognized Ags were indeed conserved across host species, because Abs specific for all three selected Ags could be detected in patient sera, rendering the identified protein Ags potential vaccine candidates.
Assuntos
Antígenos de Bactérias/isolamento & purificação , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/microbiologia , Legionella pneumophila/imunologia , Doença dos Legionários/imunologia , Administração Intranasal , Animais , Anticorpos Antibacterianos/biossíntese , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/uso terapêutico , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/imunologia , Subpopulações de Linfócitos B/metabolismo , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/síntese química , Vacinas Bacterianas/imunologia , Bacteriófago lambda/genética , Bacteriófago lambda/imunologia , Sequência Conservada/imunologia , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Legionella pneumophila/patogenicidade , Doença dos Legionários/sangue , Doença dos Legionários/prevenção & controle , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/uso terapêuticoRESUMO
This review summarizes ongoing research aimed at finding novel drugs as alternatives to traditional antibiotics. Anti-virulence approaches, phage therapy and therapeutic antibodies are strategies that may yield drugs with high specificity and narrow spectra. Several candidates are currently being evaluated in clinical trials, mostly for topical applications, but so far, none have been approved for market authorization. Candidates based on antimicrobial peptides (natural, semisynthetic and synthetic) are also being tested in clinical trials, mostly for the topical treatment of chronic infections. An alternative to the development of new antibiotics is to find potentiators of traditional antibiotics; in this respect, beta-lactamase inhibitors are already in clinical use. Novel variants are under investigation as well as efflux pump inhibitors.
Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Farmacorresistência Bacteriana , Administração Tópica , Animais , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Anticorpos Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Bactérias/crescimento & desenvolvimento , Bactérias/patogenicidade , Infecções Bacterianas/microbiologia , Vacinas Bacterianas/uso terapêutico , Bacteriófagos/metabolismo , Doença Crônica , Ensaios Clínicos como Assunto , Desenho de Fármacos , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Inibidores de beta-Lactamases , beta-Lactamases/metabolismoRESUMO
The health and economic burden of infectious diseases in general and bioterrorism in particular necessitate the development of medical countermeasures. One proven approach to reduce the disease burden and spread of pathogen is treatment with monoclonal antibodies (mAb). mAbs can prevent or reduce severity of the disease by variety of mechanisms, including neutralizing pathogen growth, limiting its spread from infected to adjacent cells, or by inhibiting biological activity of toxins, such as anthrax lethal toxin. Here, we report the production of glycosylated (pp-mAb (PA) ) and non-glycosylated (pp-mAb (PANG) ) versions of a plant-derived mAb directed against protective antigen (PA) of Bacillus anthracis in Nicotiana benthamiana plants using agroinfiltration. Both forms of the antibody were able to neutralize anthrax lethal toxin activity in vitro and protect mice against an intraperitoneal challenge with spores of B. anthracis Sterne strain. A single 180 µg intraperitoneal dose of pp-mAb (PA) or pp-mAb (PANG) provided 90% and 100% survival, respectively. When tested in non-human primates, pp-mAb (PANG) was demonstrated to be superior to pp-mAb (PA) in that it had a significantly longer terminal half-life and conferred 100% protection against a lethal dose of aerosolized anthrax spore challenge after a single 5 mg/kg intravenous dose compared to a 40% survival rate conferred by pp-mAb (PA) . This study demonstrates the potential of a plant-produced non-glycosylated antibody as a useful tool for the treatment of inhalation anthrax.
Assuntos
Antraz/terapia , Anticorpos Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antitoxinas/uso terapêutico , Toxinas Bacterianas/antagonistas & inibidores , Animais , Anticorpos Antibacterianos/genética , Anticorpos Antibacterianos/metabolismo , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/metabolismo , Antígenos de Bactérias , Antitoxinas/genética , Antitoxinas/metabolismo , Modelos Animais de Doenças , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Plantas Geneticamente Modificadas/genética , Doenças dos Primatas/terapia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Doenças dos Roedores/terapia , Análise de Sobrevida , Nicotiana/genética , Resultado do TratamentoRESUMO
INTRODUCTION: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the major endothelial receptor for oxidized low-density lipoprotein, is also involved in leukocyte recruitment. Systemic leukocyte activation in sepsis represents a crucial factor in the impairment of the microcirculation of different tissues, causing multiple organ failure and subsequently death. The aim of our experimental study was to evaluate the effects of LOX-1 inhibition on the endotoxin-induced leukocyte adherence and capillary perfusion within the intestinal microcirculation by using intravital microscopy (IVM). METHODS: We used 40 male Lewis rats for the experiments. Ten placebo-treated animals served as a control. Thirty animals received 5 mg/kg lipopolysaccharide (LPS) intravenously. Ten endotoxemic rats remained untreated. In 10 LPS animals, we administered additionally 10 mg/kg LOX-1 antibodies. Ten further LPS animals received a nonspecific immunoglobulin (rat IgG) intravenously. After 2 hours of observation, intestinal microcirculation was evaluated by using IVM; the plasma levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) were determined; and LOX-1 expression was quantified in intestinal tissue with Western blot and reverse-transcription polymerase chain reaction (PCR). RESULTS: LOX-1 inhibition significantly reduced LPS-induced leukocyte adhesion in intestinal submucosal venules (P < 0.05). At the protein and mRNA levels, LOX-1 expression was significantly increased in untreated LPS animals (P < 0.05), whereas in animals treated with LOX-1 antibody, expression of LOX-1 was reduced (P < 0.05). MCP-1 plasma level was reduced after LOX-1 antibody administration. CONCLUSIONS: Inhibition of LOX-1 reduced leukocyte activation in experimental endotoxemia. LOX-1 represents a novel target for the modulation of the inflammatory response within the microcirculation in sepsis.