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1.
Blood ; 138(22): 2256-2268, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34587242

RESUMO

SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/imunologia , COVID-19/prevenção & controle , Proteínas do Capsídeo/efeitos adversos , ChAdOx1 nCoV-19/efeitos adversos , Contaminação de Medicamentos , Vetores Genéticos/efeitos adversos , Células HEK293/imunologia , Imunoglobulina G/imunologia , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/etiologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/efeitos adversos , Adenoviridae/imunologia , Animais , Complexo Antígeno-Anticorpo/ultraestrutura , Autoanticorpos/biossíntese , Síndrome de Vazamento Capilar/etiologia , Proteínas do Capsídeo/imunologia , Linhagem Celular Transformada , ChAdOx1 nCoV-19/química , ChAdOx1 nCoV-19/imunologia , ChAdOx1 nCoV-19/toxicidade , Difusão Dinâmica da Luz , Epitopos/química , Epitopos/imunologia , Armadilhas Extracelulares/imunologia , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Vetores Genéticos/imunologia , Células HEK293/química , Humanos , Imageamento Tridimensional , Imunoglobulina G/biossíntese , Inflamação , Camundongos , Microscopia/métodos , Ativação Plaquetária , Proteômica , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/imunologia , Trombose dos Seios Intracranianos/diagnóstico por imagem , Trombose dos Seios Intracranianos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Cultura de Vírus
2.
J Voice ; 33(3): 363-369, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30224308

RESUMO

OBJECTIVES: To assess the safety and immunogenicity of a nonadjuvant human papillomavirus (HPV) type 6 L1 virus-like particle (VLP) vaccine in recurrent respiratory papillomatosis (RRP) in local Chinese patients. METHODS: Patients with RRP who had undergone surgical treatment before intramuscular administration of an escalating dose of HPV type 6 L1 VLPs (1, 5, and 25 µg at 4 weekly intervals) as part of their treatment were followed up for more than 10 years. Efficacy was assessed by detecting the vaccine-induced type-specific antibody titer, calculating the intersurgical interval, and observing recurrence or remission of papillomas after receiving the vaccine. RESULTS: Nonadjuvant HPV vaccine was generally well tolerated, with no serious vaccine-related adverse episodes. It induced seroconversion for each vaccine-related HPV type. At week 12 (4 weeks after injecting 25 µg), the vaccine-induced type-specific antibody titer was significantly high. Analysis of all patients found a significant increase in the intersurgical interval and decrease in the scores. One patient (16.7%; female) experienced complete remission. Five patients (83.3%) (two males and three females) experienced partial remission. In total, complete or partial remission was achieved in six (100%) patients. CONCLUSIONS: Administration of nonadjuvant HPV type 6 L1 VLPs vaccine to RRP was generally well tolerated and highly immunogenic.


Assuntos
Anticorpos Antivirais/sangue , Proteínas do Capsídeo/administração & dosagem , Papillomavirus Humano 6/imunologia , Imunogenicidade da Vacina , Infecções por Papillomavirus/terapia , Vacinas contra Papillomavirus/administração & dosagem , Infecções Respiratórias/terapia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Adolescente , Biomarcadores/sangue , Proteínas do Capsídeo/efeitos adversos , Proteínas do Capsídeo/imunologia , Criança , China , Ensaios Clínicos Fase I como Assunto , Feminino , Humanos , Masculino , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Indução de Remissão , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Vacinas de Partículas Semelhantes a Vírus/efeitos adversos , Vacinas de Partículas Semelhantes a Vírus/imunologia
3.
Clin Exp Nephrol ; 22(1): 151-158, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28456864

RESUMO

BACKGROUND: Dialysis patients have a suboptimal response to hepatitis B (HBV) vaccination. This study aimed to compare the immunogenicity of two vaccines: the third-generation Sci-B-Vac™ vs. the second-generation Engerix B®. The cohort included two groups of dialysis patients: naïve and previously vaccinated non-responders. Primary endpoints were antibody titers ≥10 IU/L at 3 and 7 month post-vaccination. Secondary objectives were seroprotection rates in vaccine-naïve patients and in previously vaccinated non-responders. METHODS: Eighty-six patients were assigned to vaccine (Sci-B-Vac™ or Engerix B®) using computer-generated randomization, stratified by age, gender, diabetes, and previous HBV vaccination. Sci-B-Vac™ was administered in three doses, 10 µg, at 0, 1, and 6 months in naïve patients; or 20 µg in previously vaccinated non-responders. Engerix B® included four doses, 40 µg at 0, 1, 2, and 6 months. RESULTS: Each group had 43 patients. Seroconversion was 69.8% with Engerix B® vs. 73.2% with Sci-B-Vac™. Antibody titers at 7 months were higher with Sci-B-Vac™ (266.4 ± 383.9, median 53.4) than with Engerix® (193.2 ± 328.9, median 19). However, these differences were not significant, perhaps due to a suboptimal sample size. CONCLUSIONS: This study suggests comparable immunogenicity for both vaccines. Thus, we cannot reject the null hypothesis that there is no difference in seroconversion by vaccine type. It is noteworthy that naïve patients were vaccinated with a standard dose of Sci-B-Vac™, while Engerix B® was administered at a double dose. Similarly, although mean antibody titer levels in the Sci-B-Vac™ group were higher than in the Engerix® group, this difference did not reach significance. Consequently, a future clinical trial should recruit a larger cohort of patients, using a standard double-dose protocol in both groups.


Assuntos
Proteínas do Capsídeo/imunologia , Vacinas contra Hepatite B/imunologia , Nefropatias/imunologia , Nefropatias/terapia , Diálise Renal , Idoso , Idoso de 80 Anos ou mais , Proteínas do Capsídeo/efeitos adversos , Estudos de Coortes , Feminino , Hepatite B/prevenção & controle , Vacinas contra Hepatite B/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Soroconversão
4.
Hum Gene Ther ; 28(11): 1061-1074, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28835127

RESUMO

Over the past decade, vectors derived from adeno-associated virus (AAV) have established themselves as a powerful tool for in vivo gene transfer, allowing long-lasting and safe transgene expression in a variety of human tissues. Nevertheless, clinical trials demonstrated how B and T cell immune responses directed against the AAV capsid, likely arising after natural infection with wild-type AAV, might potentially impact gene transfer safety and efficacy in patients. Seroprevalence studies have evidenced that most individuals carry anti-AAV neutralizing antibodies that can inhibit recombinant AAV transduction of target cells following in vivo administration of vector particles. Likewise, liver- and muscle-directed clinical trials have shown that capsid-reactive memory CD8+ T cells could be reactivated and expanded upon presentation of capsid-derived antigens on transduced cells, potentially leading to loss of transgene expression and immune-mediated toxicities. In celebration of the 25th anniversary of the European Society of Gene and Cell Therapy, this review article summarizes progress made during the past decade in understanding and modulating AAV vector immunogenicity. While the knowledge generated has contributed to yield impressive clinical results, several important questions remain unanswered, making the study of immune responses to AAV a priority for the field of in vivo transfer.


Assuntos
Dependovirus/genética , Terapia Genética/efeitos adversos , Vetores Genéticos/efeitos adversos , Imunidade Celular/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas do Capsídeo/efeitos adversos , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/uso terapêutico , Ensaios Clínicos como Assunto , Dependovirus/imunologia , Terapia Genética/tendências , Vetores Genéticos/uso terapêutico , Humanos
5.
Hum Vaccin Immunother ; 13(6): 1-6, 2017 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-28272989

RESUMO

We report on the design of a phase I, non-randomized, open-label study of idiotypic DNA vaccination in patients with B-cell non-Hodgkin's lymphoma (ISRCTN31090206). The study uses DNA fusion gene vaccination encoding patient-specific single chain variable fragment, or idiotype, linked to an immunostimulatory sequence. Two types of immunostimulatory sequence are being explored: potato virus X coat protein and human chemokine MIP3α. Linear polyethylenimine with low molecular weight (8 kDa) is used as a synthetic vehicle for vaccine delivery. Humoral and T-cellular immune responses to vaccination will be measured by ELISA and ELISPOT, respectively. The primary study endpoints are safety, tolerability and immunogenicity of DNA-PEI vaccination.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Linfoma de Células B/terapia , Linfoma não Hodgkin/terapia , Polietilenoimina/efeitos adversos , Vacinas de DNA/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/genética , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Proteínas do Capsídeo/administração & dosagem , Proteínas do Capsídeo/efeitos adversos , Proteínas do Capsídeo/genética , Quimiocina CCL20/administração & dosagem , Quimiocina CCL20/efeitos adversos , Quimiocina CCL20/genética , Ensaio de Imunoadsorção Enzimática , ELISPOT , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/genética , Fragmentos Fab das Imunoglobulinas/imunologia , Masculino , Pessoa de Meia-Idade , Polietilenoimina/administração & dosagem , Potexvirus/genética , Linfócitos T/imunologia , Vacinas de DNA/administração & dosagem , Adulto Jovem
6.
J Pediatr Gastroenterol Nutr ; 61(4): 400-3, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25988560

RESUMO

OBJECTIVE: Previous studies have suggested that hepatitis B virus (HBV) vaccines may be less immunogenic in individuals with celiac disease (CD). A pre-S vaccine (Sci-B-Vac) has demonstrated superior immunogenicity compared with standard HBV vaccines in several diseases. We compared the short-term immunogenicity of a pre-S vaccine with a HBV vaccine (Engerix B) for repeat vaccination of seronegative, previously immunized patients with CD. METHODS: Participants were 1 to 18-year-old children with CD who despite standard HBV vaccines in infancy had nonprotective hepatitis B surface antibody (HBs-Ab) concentrations (≤10 mIU/mL). Patients were randomized to receive either Engerix B or pre-S vaccine. HBs-Ab concentrations were measured 1 month after the first dose. For those who had not responded after 1 dose, measurement was repeated after the third dose. RESULTS: Children (n = 82) were analyzed (42 pre-S vaccine and 40 Engerix B). Baseline characteristics were similar for both groups, including gluten-free diet status. Both arms showed high response rates following the first injection: 41 (98%) versus 35 (87%) for pre-S vaccine and Engerix B recipients, respectively (P = 0.08). All other patients responded when measured after dose 3. HBs-Ab concentrations (mIU/mL) were higher in the pre-S vaccine group (median 925, interquartile range [IQR] 424-1000) than the Engerix B group (median 363, IQR 106-996, P = 0.005). Twenty (48%) of the pre-S vaccine recipients were "high responders" (>1000 mIU/mL) versus 10 (25%) in Engerix B recipients (P = 0.008). CONCLUSIONS: Both vaccines elicited adequate booster responses in most previously vaccinated patients with CD with nonprotective HBs-Ab concentrations. Pre-S vaccine administration resulted in higher Hbs-Ab concentrations. Our data suggest that a single dose of either vaccine is sufficient to raise titers to protective levels in most patients with CD.


Assuntos
Proteínas do Capsídeo/uso terapêutico , Doença Celíaca/imunologia , Anticorpos Anti-Hepatite B/análise , Antígenos de Superfície da Hepatite B/uso terapêutico , Vacinas contra Hepatite B/uso terapêutico , Hepatite B/prevenção & controle , Imunidade Ativa/efeitos dos fármacos , Imunização Secundária , Precursores de Proteínas/uso terapêutico , Centros Médicos Acadêmicos , Adolescente , Formação de Anticorpos/efeitos dos fármacos , Proteínas do Capsídeo/efeitos adversos , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Doença Celíaca/sangue , Doença Celíaca/complicações , Criança , Pré-Escolar , Método Duplo-Cego , Hepatite B/complicações , Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/efeitos adversos , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/metabolismo , Vacinas contra Hepatite B/efeitos adversos , Vacinas contra Hepatite B/genética , Vacinas contra Hepatite B/metabolismo , Humanos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Lactente , Israel , Perda de Seguimento , Precursores de Proteínas/efeitos adversos , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/metabolismo , Vacinas Sintéticas/uso terapêutico
7.
J Neuroinflammation ; 9: 60, 2012 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-22452799

RESUMO

BACKGROUND: The extent to which susceptibility to brain hemorrhage is derived from blood-derived factors or stromal tissue remains largely unknown. We have developed an inducible model of CD8 T cell-initiated blood-brain barrier (BBB) disruption using a variation of the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. This peptide-induced fatal syndrome (PIFS) model results in severe central nervous system (CNS) vascular permeability and death in the C57BL/6 mouse strain, but not in the 129 SvIm mouse strain, despite the two strains' having indistinguishable CD8 T-cell responses. Therefore, we hypothesize that hematopoietic factors contribute to susceptibility to brain hemorrhage, CNS vascular permeability and death following induction of PIFS. METHODS: PIFS was induced by intravenous injection of VP2121-130 peptide at 7 days post-TMEV infection. We then investigated brain inflammation, astrocyte activation, vascular permeability, functional deficit and microhemorrhage formation using T2*-weighted magnetic resonance imaging (MRI) in C57BL/6 and 129 SvIm mice. To investigate the contribution of hematopoietic cells in this model, hemorrhage-resistant 129 SvIm mice were reconstituted with C57BL/6 or autologous 129 SvIm bone marrow. Gadolinium-enhanced, T1-weighted MRI was used to visualize the extent of CNS vascular permeability after bone marrow transfer. RESULTS: C57BL/6 and 129 SvIm mice had similar inflammation in the CNS during acute infection. After administration of VP2121-130 peptide, however, C57BL/6 mice had increased astrocyte activation, CNS vascular permeability, microhemorrhage formation and functional deficits compared to 129 SvIm mice. The 129 SvIm mice reconstituted with C57BL/6 but not autologous bone marrow had increased microhemorrhage formation as measured by T2*-weighted MRI, exhibited a profound increase in CNS vascular permeability as measured by three-dimensional volumetric analysis of gadolinium-enhanced, T1-weighted MRI, and became moribund in this model system. CONCLUSION: C57BL/6 mice are highly susceptible to microhemorrhage formation, severe CNS vascular permeability and morbidity compared to the 129 SvIm mouse. This susceptibility is transferable with the bone marrow compartment, demonstrating that hematopoietic factors are responsible for the onset of brain microhemorrhage and vascular permeability in immune-mediated fatal BBB disruption.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Infecções por Cardiovirus/complicações , Hemorragias Intracranianas/etiologia , Animais , Astrócitos/efeitos dos fármacos , Barreira Hematoencefálica , Transplante de Medula Óssea/métodos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Proteínas do Capsídeo/efeitos adversos , Modelos Animais de Doenças , Citometria de Fluxo , Fluoresceína-5-Isotiocianato/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Hematínicos , Hemorragias Intracranianas/cirurgia , Hemorragias Intracranianas/virologia , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos , Atividade Motora/fisiologia , Teste de Desempenho do Rota-Rod , Theilovirus/patogenicidade , Proteínas Virais/efeitos adversos
10.
J Neuroimmunol ; 188(1-2): 13-21, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17493690

RESUMO

Demyelination, a pathological hallmark of multiple sclerosis, may be a necessary but not a sufficient condition for motor dysfunction associated with this disease. We favor a neurodegenerative model of multiple sclerosis and suggest that demyelination creates a permissive environment wherein the denuded axon becomes susceptible to immune-mediated injury. Unfortunately, the cellular effectors responsible for eliciting such axonal injury are currently unknown. Based on previous observations implicating cytotoxic T cells in this injury, we assessed motor function, axon dropout, and axon injury following peptide depletion of the immunodominant CD8+ antiviral T cell response in the IFNgamma receptor-deficient mouse model of acute demyelination. We found that the targeted removal of this population of cytotoxic effector cells prior to infection with the Theiler's murine encephalomyelitis virus caused a substantial preservation of motor function at 45 days postinfection that was associated with preservation of retrograde axonal transport in a subpopulation of surviving axons within the spinal cord. We conclude that cytotoxic T cells may be responsible for the initiation of axon injury following demyelination.


Assuntos
Transporte Axonal/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Proteínas do Capsídeo/efeitos adversos , Infecções por Cardiovirus/complicações , Doenças Desmielinizantes/etiologia , Atividade Motora/fisiologia , Análise de Variância , Animais , Transporte Axonal/efeitos dos fármacos , Axônios/patologia , Comportamento Animal , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Citometria de Fluxo , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Receptores de Interferon/deficiência , Teste de Desempenho do Rota-Rod/métodos , Coloração pela Prata/métodos , Receptor de Interferon gama
11.
J Immunol ; 174(11): 6854-62, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15905527

RESUMO

Peptide immunotherapy both activates and suppresses the T cell response against known peptide Ags. Although pretreatment with VP2(121-130) peptide inhibits the development of antiviral CTL specific for the immunodominant D(b):VP2(121-130) epitope expressed during acute Theiler's murine encephalomyelitis virus infection, i.v. injection of this same peptide or MHC tetramers containing the peptide during an ongoing antiviral CTL response results in a peptide-induced fatal syndrome (PIFS) within 48 h. Susceptibility to PIFS is dependent on peptide-specific CD8(+) T cells, varies among inbred strains of mice, and is not mediated by traditionally defined mechanisms of shock. Analyses using bone marrow chimeras and mutant mice demonstrate that susceptibility to PIFS is determined by the genotype of bone marrow-derived cells and requires the expression of perforin. Animals responding to peptide treatment with PIFS develop classical stress responses in the brain. These findings raise important considerations for the development of peptide therapies for active diseases to modify immune responses involving expanded populations of T cells. In summary, treatment with peptides or MHC-tetramers during a peptide-specific immune response can result in a fatal shock-like syndrome. Susceptibility to the syndrome is genetically determined, is mediated by CD8(+) T cells, and requires expression of perforin. These findings raise concerns about the use of peptides and MHC tetramers in therapeutic schemes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Proteínas do Capsídeo/efeitos adversos , Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/mortalidade , Epitopos de Linfócito T/efeitos adversos , Epitopos Imunodominantes/efeitos adversos , Theilovirus/imunologia , Animais , Apresentação de Antígeno/genética , Linfócitos T CD8-Positivos/metabolismo , Permeabilidade Capilar/genética , Permeabilidade Capilar/imunologia , Proteínas do Capsídeo/administração & dosagem , Proteínas do Capsídeo/imunologia , Infecções por Cardiovirus/genética , Infecções por Cardiovirus/fisiopatologia , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/imunologia , Feminino , Predisposição Genética para Doença/genética , Antígenos H-2/imunologia , Antígeno de Histocompatibilidade H-2D , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/fisiologia , Imunidade Inata/genética , Esquemas de Imunização , Epitopos Imunodominantes/administração & dosagem , Epitopos Imunodominantes/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/imunologia , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Síndrome , Receptor de Interferon gama
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