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1.
Indian J Gastroenterol ; 39(2): 153-160, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32468382

RESUMO

BACKGROUND: The development of anti-drug antibodies (ADA) to tumor necrosis factor (TNF-α) inhibitors is a significant result contributing to the loss of clinical response in inflammatory bowel disease (IBD). AIMS: We performed a systematic review and meta-analysis to assess whether the addition of immunomodulators to TNF-α inhibitors lead to reversal of antibody formation in TNF-α inhibitor-treated IBD patients. METHODS: We conducted a comprehensive search of electronic databases from inception through October 2018 in order to identify specific studies describing clinical response in IBD patients following the addition of immunomodulators (methotrexate or thiopurines) to TNF-α inhibitors. Clinical response was expressed as an improvement of symptoms, with a noted decrease or complete elimination of ADA against TNF-α inhibitors. The meta-analysis was performed using the DerSimonian and Laird random-effect model. RESULTS: Four studies were included in our final meta-analysis, which reported outcomes in 72 patients receiving TNF-α inhibitors. Forty-nine of the seventy-two (68%) patients received either methotrexate (19) or thiopurines (30). The average follow up period was 13.5 months. The overall pooled clinical response was 73.86% (95% confidence interval [CI] = 47.36-94.38, I2 = 60.77%). CONCLUSION: In our meta-analysis, addition of immunomodulators to TNF-α inhibitors was shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long-term multicenter studies are needed to validate these findings.


Assuntos
Anticorpos/sangue , Formação de Anticorpos/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Mercaptopurina/análogos & derivados , Metotrexato/administração & dosagem , Metotrexato/farmacologia , Inibidores do Fator de Necrose Tumoral/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacologia , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Fator de Necrose Tumoral alfa
2.
Nanotoxicology ; 14(5): 711-724, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374645

RESUMO

Prenatal particle exposure has been shown to increase allergic responses in offspring. Carbon nanotubes (CNTs) possess immunomodulatory properties, but it is unknown whether maternal exposure to CNTs interferes with offspring immune development. Here, C57Bl/6J female mice were intratracheally instilled with 67 of µg multiwalled CNTs on the day prior to mating. After weaning, tolerance and allergy responses were assessed in the offspring. Offspring of CNT-exposed (CNT offspring) and of sham-exposed dams (CTRL offspring) were intranasally exposed to ovalbumin (OVA) once weekly for 5 weeks to induce airway mucosal tolerance. Subsequent OVA sensitization and aerosol inhalation caused low or no OVA-specific IgE production and no inflammation. However, the CNT offspring presented with significantly lower OVA-specific IgG1 levels than CTRL offspring. In other groups of 5-week-old offspring, low-dose sensitization with OVA and subsequent OVA aerosol inhalation led to significantly lower OVA-specific IgG1 production in CNT compared to CTRL offspring. OVA-specific IgE and airway inflammation were non-significantly reduced in CNT offspring. The immunomodulatory effects of pre-gestational exposure to multiwalled CNTs were unexpected, but very consistent. The observations of suppressed antigen-specific IgG1 production may be of importance for infection or vaccination responses and warrant further investigation.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Antígenos/toxicidade , Hipersensibilidade/etiologia , Nanotubos de Carbono/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Antígenos/química , Feminino , Humanos , Hipersensibilidade/imunologia , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Nanotubos de Carbono/química , Ovalbumina/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
3.
Nat Med ; 26(6): 845-848, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32350462

RESUMO

We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.


Assuntos
Anticorpos Antivirais/sangue , Formação de Anticorpos/efeitos dos fármacos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Formação de Anticorpos/imunologia , Antivirais/uso terapêutico , Betacoronavirus/genética , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/virologia
5.
Res Vet Sci ; 130: 193-196, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32199178

RESUMO

Stimulation with polyclonal activators is a tool to increase antibody secretion in B cells. The aim of the present study was to select the most effective common commercially available polyclonal activators of rabbit B cells. Specifically, type B oligodeoxynucleotides with unmethylated deoxycytidyl-deoxyguanosine dinucleotides (CpG-ODN), recombinant rabbit interleukin-2 (rrIL-2), lipopolysaccharide (LPS), pokeweed mitogen (PWM) and Resiquimod (R848) were tested on B cells isolated from blood and spleen by fluorescence-activated cell sorting. Based on the obtained data, stimulation with CpG-ODN induced the highest antigen-specific antibody levels detected by ELISA in supernatants when a single activator was used. In contrast, LPS, PWM and R848 showed a weak or no stimulatory effect. Stimulation with a mix of activators was more effective than CpG-ODN alone, which indicates a synergistic effect in the stimulation of antibody production.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Linfócitos B/imunologia , Oligodesoxirribonucleotídeos/imunologia , alfa-Macroglobulinas/imunologia , Animais , Feminino , Masculino , Oligodesoxirribonucleotídeos/administração & dosagem , Coelhos , alfa-Macroglobulinas/administração & dosagem
6.
Mar Drugs ; 18(3)2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32168741

RESUMO

Thе study presents the results of a comparative evaluation of the effect of structural modifications of fucoidans from the brown alga Fucus evanescens (native, highly purified рroduct of fucoidan enzymatic hydrolysis, a new regular 1→3;1→4-α-L-fucan, sulphated mainly at C2 and acetylated at C4 of the fucose residue) on the effector functions of innate and adaptive immunity cells in vitro and in vivo. Using flow cytometry, we found that all examined fucoidans induce the maturation of dendritic cells, enhance the ability of neutrophils to migrate and adhere, activate monocytes and enhance their antigen-presenting functions, and increase the cytotoxic potential of natural killers. Fucoidans increase the production of hepatitis B virus (HBs) specific IgG and cytokine Th1 (IFN-γ, TNF-α) and Th2 (IL-4) profiles in vivo. The data obtained suggest that in vitro and in vivo adjuvant effects of the products of fucoidan enzymatic hydrolysis with regular structural characteristics are comparable to those of the native fucoidan. Based on these data, the products of fucoidan enzymatic hydrolysis can be considered as an effective and safe candidate adjuvant to improve the efficacy of prophylactic and therapeutic vaccines.


Assuntos
Adjuvantes Imunológicos/farmacologia , Fucus/química , Polissacarídeos/farmacologia , Imunidade Adaptativa/efeitos dos fármacos , Adjuvantes Imunológicos/química , Animais , Formação de Anticorpos/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Polissacarídeos/química , Relação Estrutura-Atividade
7.
J Med Chem ; 63(6): 3290-3297, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32101001

RESUMO

We have prepared a number of saponin-based vaccine adjuvant candidates. These unnatural saponins have a different terminal-functionalized side chain incorporated into the glucuronic acid unit that is attached to a triterpenoid core at its C3 position. The semisynthetic saponin adjuvants have shown significantly different immunostimulatory activities, suggesting that the structure of the side chain, triterpenoid core, and oligosaccharide domain together orchestrate saponin adjuvant's potentiation of immune responses. Among these new adjuvant candidates, VSA-2 (5b), a derivative of Momordica saponin (MS) II, showed consistent enhancement of immunoglobulin G2a (IgG2a) production when it was in formulation with either ovalbumin or recombinant hemagglutinin B (rHagB) antigen. With rHagB antigen, it induced a significantly higher IgG2a response than the positive control GPI-0100, a well-studied semisynthetic saponin adjuvant mixture derived from Quillaja saponaria Molina saponins, known for its ability to induce a balanced Th1/Th2 immunity. These results confirm that Momordica saponins are a viable natural source to provide potent saponin adjuvants after simple chemical derivatization and identify VSA-2 (5b) as another MS-based promising immunostimulant lead owing to its distinctive ability in potentiating the IgG2a response.


Assuntos
Adjuvantes Imunológicos/farmacologia , Saponinas/farmacologia , Adesinas Bacterianas/imunologia , Adjuvantes Imunológicos/síntese química , Animais , Formação de Anticorpos/efeitos dos fármacos , Galinhas , Feminino , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Lectinas/imunologia , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ovalbumina/imunologia , Saponinas/síntese química , Saponinas/imunologia , Células Th1/efeitos dos fármacos
8.
Sci Rep ; 10(1): 3229, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094377

RESUMO

Diabetes mellitus (DM) patients are at an increased risk of complications following influenza-virus infection, seasonal vaccination (SV) is recommended. However, SV with trivalent influenza vaccine (TIV) can induce antibody and type-I interferon (IFN) responses, and the effect of anti-DM treatment on these responses is incompletely understood. We evaluated the antibody response and IFN-α expression in individuals with and without type 2 DM (T2DM) following SV, and examined the effects on anti-DM treatment. TIV elicited sero-protection in all groups, but antibody persistency was <8 months, except for the antibody response to B-antigens in non-DM. T2DM impaired the IgG avidity index, and T2DM showed a significantly decreased response against H1N1 and H3N2, in addition to delaying and reducing haemagglutination-inhibition persistency against influenza B-antigens in DM groups treated with metformin (Met-DM) or glibenclamide (GB-DM). Following TIV, the Met-DM and GB-DM groups exhibited reduced IFN-α expression upon stimulation with whole- and split-virion influenza vaccines. Suppression of IFN-α expression in the Met-DM group was associated with a reduction in the mechanistic target of rapamycin complex-1 pathway and impaired IgG avidity index. Thus, single-dose TIV each year might not be suitable for T2DM. Our data could aid the development of an efficacious influenza vaccine for T2DM.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Diabetes Mellitus Tipo 2/imunologia , Interferon-alfa/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metformina/farmacologia , Estações do Ano , Transdução de Sinais , Vacinação , Idoso , Anticorpos Antivirais/imunologia , Afinidade de Anticorpos/imunologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Glibureto/farmacologia , Glibureto/uso terapêutico , Testes de Inibição da Hemaglutinação , Humanos , Imunoglobulina G/metabolismo , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/imunologia , Vacinas contra Influenza/imunologia , Masculino , Metformina/uso terapêutico , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vírion/efeitos dos fármacos , Vírion/imunologia
9.
PLoS One ; 15(2): e0228463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027689

RESUMO

Infection with Brucella abortus causes contagious zoonosis, brucellosis, and leads to abortion in animals and chronic illness in humans. Chitosan nanoparticles (CNs), biocompatible and nontoxic polymers, acts as a mucosal adjuvant. In our previous study, B. abortus malate dehydrogenase (Mdh) was loaded in CNs, and it induced high production of pro-inflammatory cytokines in THP-1 cells and systemic IgA in BALB/C mice. In this study, the time-series gene expression analysis of nasal-associated lymphoid tissue (NALT) was performed to identify the mechanism by which Mdh affect the target site of nasal immunization. We showed that intranasal immunization of CNs-Mdh reduced cell viability of epithelial cells and muscle cells at first 1 h, then induced cellular movement of immune cells such as granulocytes, neutrophils and lymphocytes at 6h, and activated IL-6 signaling pathway at 12h within NALT. These activation of immune cells also promoted signaling pathway for high-mobility group box 1 protein (HMGB1), followed by the maturation of DCs required for mucosal immunity. The CNs also triggered the response to other organism and inflammatory response, showing it is immune-enhancing adjuvant. The ELISA showed that significant production of specific IgA was detected in the fecal excretions and genital secretions from the CNs-Mdh-immunized group after 2 weeks-post immunization. Collectively, these results suggest that B. abortus Mdh-loaded CNs triggers activation of HMGB1, IL-6 and DCs maturation signaling within NALT and induce production of systemic IgG and IgA.


Assuntos
Formação de Anticorpos/fisiologia , Brucella abortus/imunologia , Brucelose/prevenção & controle , Imunização/métodos , Tecido Linfoide/imunologia , Malato Desidrogenase/imunologia , Administração Intranasal , Animais , Formação de Anticorpos/efeitos dos fármacos , Brucella abortus/metabolismo , Brucelose/imunologia , Quitosana/administração & dosagem , Quitosana/química , Quitosana/imunologia , Quitosana/farmacologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Imunidade nas Mucosas/efeitos dos fármacos , Imunogenicidade da Vacina , Tecido Linfoide/efeitos dos fármacos , Malato Desidrogenase/administração & dosagem , Malato Desidrogenase/metabolismo , Malato Desidrogenase/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia
10.
Immunol Med ; 43(2): 87-91, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31994996

RESUMO

Abatacept may exert its clinical effect on rheumatoid arthritis (RA) by suppressing anti-cyclic citrullinated peptide (CCP) antibody production. This study was undertaken to test this hypothesis by examining the changes of disease activity of RA and anti-CCP antibody levels over time after starting abatacept. Sixty Japanese RA patients who started abatacept were included in this multicenter, prospective observational study. Simple Disease Activity Index (SDAI) and anti-CCP antibody levels were evaluated at 12, 24, and 52 weeks. The mean SDAI score significantly decreased within 12 weeks after starting abatacept and was maintained thereafter. On the contrary, the mean anti-CCP antibody levels did not change until 52 weeks. At the individual level, there were substantial changes of anti-CCP antibody levels, but these were not correlated with the changes of disease activity at any time points. Thus, abatacept reduces the disease activity of RA independently of modulating anti-CCP antibody production.


Assuntos
Abatacepte/uso terapêutico , Anticorpos Anti-Proteína Citrulinada/metabolismo , Formação de Anticorpos/efeitos dos fármacos , Artrite Reumatoide/dietoterapia , Artrite Reumatoide/imunologia , Abatacepte/farmacologia , Idoso , Anticorpos Anti-Proteína Citrulinada/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Microb Pathog ; 140: 103932, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31857237

RESUMO

Today's, vaccination is the most cost-effective approaches for preventing infectious diseases. In this strategy, adjuvants play an important role. Propolis from honey bee can stimulate the immune system and several studies have shown the modulating effects of Propolis on the immune responses. Here, the adjuvant effects of aqueous and alcoholic extracts of Propolis were studied on the multi-epitope vaccines against HIV-1. A recombinant vaccine against HIV-1 was prepared and BALB/c mice were immunized. subcutaneously on day 0 with 100 µl of candidate vaccine (10 µg) formulated in an alcoholic extract of Propolis. The second group of mice was immunized with the vaccine (10 µg) formulated in aqueous extract of Propolis. Also, candidate vaccine was formulated in Freund's and Alum adjuvants in the third and fourth groups. Experimental mice were immunized three times with two week intervals under the same conditions and suitable control groups. After final injection, lymphocyte proliferation was measured by BrdU method, IL-4 and IFN-γ cytokines, specific total IgG antibodies, IgG1 and IgG2a isotypes were evaluated using ELISA. The results show that the aqueous and alcoholic extracts were able to enhance lymphocyte proliferation, IL-4 and IFN-γ cytokines and antibody responses with dominant IgG1 pattern and comparable to Freund's and Alum adjuvants. It seems that aqueous and alcoholic extracts of Propolis show adjuvant activity and may be useful for vaccine formulation.


Assuntos
Adjuvantes Imunológicos/farmacologia , HIV-1/imunologia , Própole/farmacologia , Compostos de Alúmen/farmacologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Adjuvante de Freund/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Sintéticas/imunologia
13.
Eur J Immunol ; 50(1): 73-85, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31621069

RESUMO

Antibody production by the B cell compartment is a crucial part of the adaptive immune response. Dysregulated antibody production in the form of autoantibodies can cause autoimmune disease. To date, B-cell depletion with anti-CD20 antibodies is commonly applied in autoimmunity, but pre-existing plasma cells are not eliminated in this way. Alternative ways of more selective inhibition of antibody production would add to the treatment of these autoimmune diseases. To explore novel therapeutic targets in signaling pathways essential for plasmablast formation and/or immunoglobulin production, we performed a compound screen of almost 200 protein kinase inhibitors in a robust B-cell differentiation culture system. This study yielded 35 small cell-permeable compounds with a reproducible inhibitory effect on B-cell activation and plasmablast formation, among which was the clinically applied mammalian target of rapamycin (mTOR) inhibitor rapamycin. Two additional compounds targeting the phosphoinositide 3-kinase-AKT-mTOR pathway (BKM120 and WYE-354) did not affect proliferation and plasmablast formation, but specifically reduced the immunoglobulin production. With this compound screen we successfully applied a method to investigate therapeutic targets for B-cell differentiation and identified compounds in the phosphoinositide 3-kinase-AKT-mTOR pathway that could specifically inhibit immunoglobulin production only. These drugs may well be explored to be of value in current B-cell-depleting treatment regimens in autoimmune disorders.


Assuntos
Autoanticorpos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Plasmócitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Aminopiridinas/farmacologia , Formação de Anticorpos/efeitos dos fármacos , Autoanticorpos/biossíntese , Doenças Autoimunes/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Diferenciação Celular/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Morfolinas/farmacologia , Plasmócitos/imunologia , Purinas/farmacologia , Sirolimo/farmacologia
14.
Aliment Pharmacol Ther ; 51(3): 356-363, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31650614

RESUMO

BACKGROUND: Anti-drug antibodies (ADAs) are a leading contributor to infliximab loss of response and adverse drug events. It is not feasible to identify patients at risk of antibody formation before initiating infliximab. The genetic variation HLADQA1*05 (rs2097432) has been linked to infliximab antibody formation in Crohn's disease (CD). AIMS: To evaluate the association between HLADQA1*05 and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events in patients with inflammatory bowel disease (IBD) METHODS: In a retrospective cohort study, infliximab-exposed patients with IBD (n = 262) were screened for the genetic variation, HLADQA1*05A>G (rs2097432). Risk of infliximab ADA formation, infliximab loss of response, adverse events and discontinuation were assessed in wild-type (GG) and variant-carrying (AG or AA) individuals. RESULTS: Forty per cent of all participants were HLADQA1*05A>G variant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>G variant carriers (adjusted HR = 7.29, 95% confidence interval (CI) = 2.97-17.191, P = 1.46 × 10-5 ) independent of age, sex, weight, dose and co-immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (adjusted HR = 2.34, 95% CI = 1.41-3.88, P = .001) and discontinuation (adjusted HR = 2.27, 95% CI = 1.46-3.43, P = 2.53 × 10-4 ) although not with infliximab-associated adverse drug events. CONCLUSIONS: HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. There may be a role for genotype-guided application of combination therapy in IBD.


Assuntos
Formação de Anticorpos/genética , Resistência a Medicamentos , Cadeias alfa de HLA-DQ/genética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Infliximab/imunologia , Infliximab/uso terapêutico , Adulto , Anticorpos/metabolismo , Formação de Anticorpos/efeitos dos fármacos , Estudos de Coortes , Resistência a Medicamentos/genética , Resistência a Medicamentos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/imunologia , Masculino , Testes Farmacogenômicos , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
15.
Clin Cancer Res ; 26(4): 787-792, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757876

RESUMO

The generation of antibodies following exposure to therapeutic drugs has been widely studied, however in oncology, data in relation to their clinical relevance are limited. Antidrug antibodies (ADAs) can cause a decrease in the amount of drug available, resulting in some cases in decreased antitumor activity and a consequent impact on clinical outcomes. Several immunologic factors can influence the development of ADAs, and in addition, the sensitivity of the different testing methods used in different studies can vary, representing an additional potential confounding factor. The reported frequency of ADA-positive patients following treatment with immune checkpoint inhibitors varies from as low as 1.5% for pembrolizumab to 54% for atezolizumab. This latter drug is the only immune checkpoint inhibitor to have undergone an expanded analysis of the clinical implications of ADAs, but with discordant results. Given that immune checkpoint inhibitors can modify the immune response and potentially impact ADA formation, data from published as well as prospective trials need to be evaluated for a better understanding of the clinical implications of ADAs in this setting.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos/imunologia , Antineoplásicos Imunológicos/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Anticorpos Monoclonais/administração & dosagem , Formação de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/patologia , Prognóstico
16.
Nat Med ; 25(9): 1402-1407, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501610

RESUMO

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


Assuntos
Anticorpos Neutralizantes/administração & dosagem , Epitopos de Linfócito T/imunologia , Esclerose Múltipla/tratamento farmacológico , Natalizumab/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Neutralizantes/química , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Linfócitos B/efeitos dos fármacos , Humanos , Imunoglobulina G/química , Imunoglobulina G/imunologia , Integrina alfa4/antagonistas & inibidores , Integrina alfa4/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Conformação Proteica/efeitos dos fármacos , Linfócitos T/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
17.
J Anim Sci ; 97(10): 4362-4369, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31504608

RESUMO

This study utilized 204 Angus-based beef steers (249 ± 23 kg SD) from a single ranch with initial serum α-tocopherol concentrations of 3.9 ± 1.0 mg/L to determine the effect of varying doses of vitamin E (VE) on feedlot performance, antibody response to vaccination, and antioxidant defense. Seven days after arrival, steers were blocked by body weight and weaning protocol (preweaned, unweaned heavy, and unweaned light) and randomly assigned to pens within blocks (12 pens per block). Preweaned steers had been weaned for approximately 35 d prior to arrival, and unweaned steers were weaned when leaving the origin ranch. Pens within block were randomly assigned to supplemental VE (ROVIMIX E-50 Adsorbate, DSM Nutritional Products, Heerlen, The Netherlands) treatments (n = 9 pens per treatment): no supplemental VE (CON), 25 IU/kg dry matter (DM; LOW), 500 IU per steer daily (MED), or 1,000 IU per steer daily (HIGH). Back-calculated supplemental VE intake was 0, 151 (24.8 IU/kg DM), 484, and 995 IU/d for CON, LOW, MED, and HIGH, respectively. On day 6, all steers received a booster vaccine against bovine viral diarrhea virus (BVDV; Bovi-Shield Gold, One Shot, Zoetis, Parsippany, NJ). Steers were weighed on day -1, 0, 14, 26, and 27. One steer per pen representative of the average body weight of the pen was chosen as a sampling animal for blood (day -1, 6, 14, 26, and 28) and liver (day -3 and 24). Data were analyzed as a randomized complete block design using Proc Mixed of SAS with pen as the experimental unit and the fixed effects of treatment and block. Linear, quadratic, and cubic contrast statements were constructed using Proc IML; morbidity data were analyzed using Proc Glimmix. Day 24 liver and day 26 serum α-tocopherol concentrations were linearly increased by supplemental VE (P < 0.01). Supplemental VE did not affect DM intake, average daily gain, or gain:feed from day 0 to 27 (P ≥ 0.37), or the percentage of steers treated for respiratory disease (P ≥ 0.44). Day 24 liver glutathione concentrations decreased linearly due to supplemental VE (P ≤ 0.02). Total- and Mn-superoxide dismutase activities were quadratically affected by supplemental VE (P ≤ 0.07), with MED steers exhibiting the greatest activity. Over time, BVDV type 1 and 2 antibody titers numerically decreased, whereas the decrease in BVDV type 1 titers was lesser for HIGH steers (linear P = 0.04). Increasing doses of VE improved VE status but did not affect overall receiving period performance in steers with minimal to adequate VE status upon arrival.


Assuntos
Antioxidantes/farmacologia , Bovinos/fisiologia , Suplementos Nutricionais/análise , Vacinação/veterinária , Vitamina E/farmacologia , Ração Animal/análise , Animais , Formação de Anticorpos/efeitos dos fármacos , Peso Corporal , Bovinos/crescimento & desenvolvimento , Bovinos/imunologia , Dieta/veterinária , Fígado/efeitos dos fármacos , Masculino , Distribuição Aleatória , Desmame
18.
Int Immunopharmacol ; 75: 105756, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344556

RESUMO

Long-term graft survival after organ transplantation is difficult to achieve because of the development of chronic rejection. One cause of chronic rejection arises from antibody-mediated rejection (AMR), which is dependent on the production of donor-specific antibodies (DSA). Current immunosuppression in organ transplantation is effective in preventing acute T cell-mediated rejection, but the risk of DSA production and graft loss due to AMR remains unchanged. Phosphatidylinositol-3-kinase p110δ (PI3Kδ), a member of the family of PI3K lipid kinases, is a key mediator of B cell activation, proliferation and antibody production. AS2541019 is a novel PI3Kδ selective inhibitor that prevents antibody production by inhibiting B cell immunity. The purpose of this study was to evaluate the inhibitory effect of AS2541019 on DSA production in preclinical rodent and non-human primate allotransplant models. Concomitant administration of AS2541019 with tacrolimus and mycophenolate mofetil (MMF) inhibited de novo DSA production in an ACI-to-Lewis rat cardiac allotransplant model. To predict the efficacy of AS2541019 in clinical practice, we evaluated its effects in cynomolgus monkeys. AS2541019 inhibited B cell proliferation and major histocompatibility complex (MHC) class II expression on B cells in cynomolgus monkeys. Oral administration of AS2541019 inhibited MHC class II expression on peripheral B cells and anti-tetanus toxoid antibody production. In cynomolgus monkey renal allotransplant model, concomitant administration of AS2541019 with tacrolimus and MMF significantly inhibited de novo DSA production. Together, our findings indicate that the PI3Kδ selective inhibitor AS2541019 is a potential candidate for preventing AMR development by inhibiting DSA production.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Transplante de Coração , Transplante de Rim , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Memória Imunológica , Imunossupressores/farmacologia , Macaca fascicularis , Masculino , Ácido Micofenólico/farmacologia , Ratos , Ratos Endogâmicos ACI , Ratos Endogâmicos Lew , Tacrolimo/farmacologia , Toxoide Tetânico/administração & dosagem
19.
J Immunotoxicol ; 16(1): 149-154, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31290717

RESUMO

Although T-cell-dependent antibody response (TDAR) assays with keyhole limpet hemocyanin (KLH) as specific antigen have many advantages, most experiments produce qualitative results based on antibody titers. It was hypothesized that if experimental conditions (like antigen coating concentration, serum dilution, and detecting [here, horseradish peroxidase-goat anti-mouse IgG] antibody dilution) could be optimized, the resulting measured value (here, optical density) could be used to directly analyze and evaluate the experimental results. This means specifically that the assay OD values could be used for approximate quantitative statistical analysis; it does not require a further conversion of the data into qualitative forms or require obtaining further titer data from additional experiments. As such, the use of this "improved" assay would: greatly reduce the complexity of experimental operations; improve overall sensitivity and practicality of traditional TDAR assays; and, allow for direct assessing of any immunosuppression caused by a test drug in a host. Here, KLH-immunized serum was obtained from BALB/c mice, and the means to detect serum anti-KLH antibodies by an indirect ELISA were optimized. The results indicated that in this system, the optimal KLH coating concentration was 80 µg/ml, the optimal dilution range of the serum (at immunization dose of 5 mg KLH/kg) was 1:200-1:800, and the optimal dilution of HRP-goat anti-mouse IgG antibody was 1:16,000. Methodology verification was performed and a regression model of y = 144.16x + 0.9815 (R2 = 0.9571, indicating very good linearity) was obtained. Intragroup precision was 7.51-9.40%; the intergroup coefficient of variation was 9.83-14.22%. The lower limit of detection was 0.1385. The present results showed this indirect ELISA exhibited very good linearity, accuracy, and precision.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Bioensaio/métodos , Hemocianinas/imunologia , Imunoglobulina G/sangue , Linfócitos T/efeitos dos fármacos , Adjuvantes Imunológicos/toxicidade , Animais , Formação de Anticorpos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Hemocianinas/administração & dosagem , Hemocianinas/toxicidade , Imunoglobulina G/imunologia , Imunoglobulina G/isolamento & purificação , Limite de Detecção , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Sensibilidade e Especificidade , Linfócitos T/imunologia , Testes de Toxicidade/métodos
20.
Curr HIV Res ; 17(2): 134-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309891

RESUMO

BACKGROUND: Viral kinetics impact humoral immune response to HIV; antibody avidity testing helps distinguish recent (<6 months) and long-term HIV infection. This study aims to determine the frequency of recent HIV-1 infection among clients attending ICTC (Integrated Counselling and Testing Centre) using a commercial EIA, to correlate it with a modified in-house avidity assay and to study the impact of ART on anti-HIV-1 antibody maturation. METHODS: Commercial LAg Avidity EIA was used to detect antibody avidity among 117 treatment naïve HIV-1 infected individuals. A second-generation HIV ELISA was modified for in-house antibody avidity testing and cutoff was set based on Receiver Operating Characteristic (ROC) analysis. Archived paired samples from 25 HIV-1 infected individuals before ART and after successful ART; samples from 7 individuals responding to ART and during virological failure were also tested by LAg Avidity EIA. RESULTS: Six individuals (5.1%) were identified as recently infected by a combination of LAg avidity assay and HIV-1 viral load testing. The modified in-house avidity assay demonstrated sensitivity and specificity of 100% and 98.2%, respectively, at AI=0.69 by ROC analysis. Median ODn values of individuals when responding to ART were significantly lower than pre-ART [4.136 (IQR 3.437- 4.827) vs 4.455 (IQR 3.748-5.120), p=0.006] whereas ODn values were higher during virological failure [4.260 (IQR 3.665 - 4.515) vs 2.868 (IQR 2.247 - 3.921), p=0.16]. CONCLUSION: This modified in-house antibody avidity assay is an inexpensive method to detect recent HIV-1 infection. ART demonstrated significant effect on HIV-1 antibody avidity owing to changes in viral kinetics.


Assuntos
Antirretrovirais/farmacologia , Afinidade de Anticorpos/imunologia , Formação de Anticorpos/efeitos dos fármacos , Anticorpos Anti-HIV/imunologia , Infecções por HIV/diagnóstico , HIV-1 , Antirretrovirais/uso terapêutico , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática/normas , Anticorpos Anti-HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Sensibilidade e Especificidade
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