RESUMO
Prenatal diagnosis (preDx) of critical congenital heart disease (CCHD) decreases neonatal morbidity and mortality. Obstetrical fetal cardiac imaging guidelines in 2013 aimed to increase preDx. The objectives of this study were to determine the contemporary preDx rate of CCHD and identify maternal-fetal factors and variations in prenatal care that may be potential barriers. This retrospective single center study evaluated maternal demographics and characteristics of infants with CCHD (requiring cardiac catheterization or surgical intervention before 6 months-old) between 2016 and 2019. 58% of the 339 infants with CCHD had preDx. Infants with preDx were more likely to have mothers ≥ 35 years-old (p = 0.028), family history of CHD (p = 0.017), health insurance (p = 0.002), or anatomic scan with perinatology (p < 0.001). Hispanic infants were less likely to have preDx (45.6%, p = 0.005). PreDx rates were higher in infants with extracardiac/genetic anomalies (p < 0.001) and significantly different between CCHD subtypes (76% for single ventricle, 51% for biventricular/four-chamber view, 59% for proximal outflow tract anomalies, and 48% for distal great artery anomalies; p = 0.024). In infants without preDx, 25% of their mothers had indication for, but did not undergo, fetal echocardiography. PreDx rates of CCHD remains inadequate across subtypes detectable by standard fetal cardiac screening views, particularly in uninsured and Hispanic communities.
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Guidelines for management of Melody transcatheter pulmonary valve (TPV) infective endocarditis (IE) are lacking. We aimed to identify factors associated with surgical valve removal versus antimicrobial therapy in Melody TPV IE. Multicenter retrospective analysis of all patients receiving Melody TPV from 10/2010 to 3/2019 was performed to identify cases of IE. Surgical explants versus non-surgical cases were compared. Of the 663 Melody TPV implants, there were 66 cases of IE in 59 patients (59/663, 8.8%). 39/66 (59%) were treated with IV antimicrobials and 27/66(41%) underwent valve explantation. 26/59 patients (44%) were treated medically without explantation or recurrence with average follow-up time of 3.5 years (range:1-9). 32% of Streptococcus cases, 53% of MSSA, and all MRSA cases were explanted. 2 of the 4 deaths had MSSA. CART analysis demonstrated two important parameters associated with explantation: a peak echo gradient ≥ 47 mmHg at IE diagnosis(OR 10.6, p < 0.001) and a peak echo gradient increase of > 24 mmHg compared to baseline (OR 6.7, p = 0.01). Rates of explantation varied by institution (27 to 64%). In our multicenter experience, 44% of patients with Melody IE were successfully medically treated without valve explantation or recurrence. The degree of valve stenosis at time of IE diagnosis was strongly associated with explantation. Rates of explantation varied significantly among the institutions.
Assuntos
Endocardite Bacteriana , Endocardite , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Insuficiência da Valva Pulmonar , Valva Pulmonar , Cateterismo Cardíaco/efeitos adversos , Endocardite/etiologia , Endocardite/cirurgia , Endocardite Bacteriana/tratamento farmacológico , Endocardite Bacteriana/cirurgia , Próteses Valvulares Cardíacas/efeitos adversos , Implante de Prótese de Valva Cardíaca/efeitos adversos , Humanos , Desenho de Prótese , Valva Pulmonar/cirurgia , Insuficiência da Valva Pulmonar/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Among breast cancer survivors, low social support is associated with adverse clinical and psychosocial outcomes. This study prospectively examined longitudinal trends in perceived social support in women with newly diagnosed breast cancer as a function of depression status prior to initiation of cancer treatment. METHODS: One hundred ten patients with newly diagnosed breast cancer and 59 age-matched noncancer controls completed behavioral measures at four assessments: prior to treatment and at 1 month, 1 year, and 2 years post-treatment. Participants reported their perceived tangible and emotional/informational support using the Medical Outcomes Study Social Support Survey and were categorized as "depressed" or "non-depressed" based on the Brief Symptom Inventory-18 (BSI-18). Analyses first compared longitudinal trends in support between patients and controls and then examined differences in longitudinal trends as a function of depression status in patients only, controlling for key covariates. RESULTS: Both tangible and emotional/informational support decreased among breast cancer patients but increased or remained unchanged among noncancer controls across the assessments. Among patients, depressed individuals experienced a significant decline in both tangible (P = 0.004) and emotional/informational support (P = 0.013) between 1 month and 1 year post-treatment, which remained unchanged between 1 year and 2 years post-treatment. In contrast, nondepressed individuals had stable levels across all assessments. Depressed patients also had lower levels of both support types compared with nondepressed patients across all assessments. CONCLUSIONS: Breast cancer patients with depressive symptomatology have an elevated risk for declines in perceived social support over time.
Assuntos
Neoplasias da Mama/psicologia , Sobreviventes de Câncer/psicologia , Depressão/psicologia , Qualidade de Vida/psicologia , Apoio Social , Adulto , Atitude Frente a Saúde , Neoplasias da Mama/complicações , Estudos de Casos e Controles , Cognição , Depressão/etiologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal ß-amyloid (Aß42) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Aß42 is a target. Here, we directly compare the efficacy of anti-Aß42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6-6.5 months for preventive vaccinations and 16-19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Aß antibodies, significantly reducing pathologic forms of Aß in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11-11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Aß antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance.
Assuntos
Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Vacinas/imunologia , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Animais , Anticorpos/imunologia , Astrócitos/imunologia , Astrócitos/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Epitopos/imunologia , Imunização , Camundongos , Camundongos Transgênicos , Neuroglia/imunologia , Neuroglia/metabolismo , Fragmentos de Peptídeos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Vacinas/administração & dosagemRESUMO
The Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aß peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aß antibodies failed to slow cognitive decline in mild to moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. Using an AD mouse model (Tg2576), we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. We found that Lu AF20513 induces robust "non-self" T-cell responses and the production of anti-Aß antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or cerebral amyloid angiopathy. A single immunization with Lu AF20513 induced strong humoral immunity in mice with preexisting memory T-helper cells. In addition, Lu AF20513 induced strong humoral responses in guinea pigs and monkeys. These data support the translation of Lu AF20513 to the clinical setting with the aims of: (1) inducing therapeutically potent anti-Aß antibody responses in patients with mild AD, particularly if they have memory T-helper cells generated after immunizations with conventional tetanus toxoid vaccine, and (2) preventing pathological autoreactive T-cell responses.
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Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/química , Epitopos de Linfócito T/imunologia , Fragmentos de Peptídeos/química , Vacinação/métodos , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Anti-Idiotípicos/farmacologia , Formação de Anticorpos/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/metabolismo , Feminino , Cobaias , Humanos , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Transgênicos , Mutação/genética , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Ligação Proteica/imunologia , Ressonância de Plasmônio de Superfície , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinas/imunologiaRESUMO
BACKGROUND: Previously we demonstrated that the resection of primary 4T1 tumors only slightly prolongs mouse survival, but importantly, creates a "window of opportunity" with attenuated suppressor cell and increased activated T cell populations. This suggests that additional activation of the immune system by immunostimulatory agents during this period may enhance anti-tumor immunity and potentially eradicate micro-metastatic disease in this stringent model. We hypothesized that the immunostimulator Immunomax®, which is comprised of a plant-derived polysaccharide, is non-toxic in humans and stimulates immune defense during the infectious diseases treatment, may have also anti-tumor activity and be beneficial in the adjuvant setting when endogenous anti-tumor responses are present and during the "window of opportunity" in post-resection metastatic breast cancer model. Here we provide the initial report that Immunomax® demonstrates the capacity to eliminate micro-metastatic disease in the post-resection, 4T1 mouse model of breast cancer. METHODS: The efficacy of Immunomax® was evaluated by analyzing survival rate and the number of spontaneous clonogenic tumor cells in the lung homogenates of mice. The frequencies of activated NK, CD4(+) and CD8(+) cells as well as myeloid-derived suppressor cells and Treg cells were evaluated using flow cytometry. Highly purified mouse and human dendritic and NK cells were sorted and the effect of Immunomax® on activation status of these cells was assessed by flow cytometry. The property of Immunomax® as TLR-4 agonist was determined by NF-κB/SEAP reporter gene assay, WB, RT-PCR. RESULTS: Immunomax® injections significantly prolonged overall survival and cured 31% of mice. This immunostimulator activates DCs via the TLR-4, which in turn stimulates tumoricidal NK cells and in vitro, completely inhibits growth of 4T1 cells. Incubation of PBMC from healthy donors with Immunomax® activates NK cells via activation of plasmacytoid DC leading significantly higher efficacy in killing of human NK-target cells K562 compared with non-treated cells. CONCLUSION: This is the first demonstration that Immunomax® is a TLR-4 agonist and the first report of a documented role for this pharmaceutical grade immunostimulator in augmenting anti-tumor activity, suggesting that incorporation of Immunomax® into developing breast cancer therapeutic strategies may be beneficial and with less potential toxicity than checkpoint inhibitors.
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Neoplasias Mamárias Experimentais/terapia , Metástase Neoplásica , Extratos Vegetais/farmacologia , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Feminino , Linfócitos/imunologia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: As a prelude to clinical trials we have characterized B- and T-cell immune responses in macaques to AD vaccine candidates: AV-1955 and its slightly modified version, AV-1959 (with 3 additional promiscuous Th epitopes). METHODS: T- and B-cell epitope mapping was performed using the ELISPOT assay and competition ELISA, respectively. RESULTS: AV-1955 and AV-1959 did not stimulate potentially harmful autoreactive T cells, but instead activated a broad but individualized repertoire of Th cells specific to the MultiTEP platform in macaques. Although both vaccines induced robust anti-Aß antibody responses without producing antibodies specific to Th epitopes of MultiTEP platforms, analyses of cellular immune responses in macaques demonstrated that the addition of Th epitopes in the case of AV-1959 created a more potent, superior vaccine. CONCLUSION: AV-1959 is a promising vaccine candidate capable of producing therapeutically potent anti-amyloid antibody in a broader population of vaccinated subjects with high MHC class II gene polymorphisms.
Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Vacinas contra Alzheimer/imunologia , Vacinas contra Alzheimer/uso terapêutico , Ativação Linfocitária , Peptídeos beta-Amiloides/imunologia , Animais , Anticorpos/imunologia , Formação de Anticorpos , Linfócitos B/imunologia , Ensaio de Imunoadsorção Enzimática , ELISPOT , Mapeamento de Epitopos , Epitopos de Linfócito B , Epitopos de Linfócito T , Feminino , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de DNA/uso terapêuticoRESUMO
BACKGROUND: Clinical trials with passive and active Alzheimer's disease (AD) vaccines suggest that early interventions are needed for improvement of cognitive and/or functional performance in patients, providing impetus for the development of safe and immunologically potent active vaccines targeting amyloid ß (Aß). The AN-1792 trial has indicated that Aß-specific T cells may be unsafe for humans; therefore, other vaccines based on small Aß epitopes are undergoing preclinical and clinical testing. METHODS: Humoral and cellular immune responses elicited in response to a novel DNA epitope-based vaccine (AV-1955) delivered to rhesus macaques using the TriGrid electroporation device were evaluated. Functional activities of anti-Aß antibodies generated in response to vaccination were assessed in vitro. RESULTS: AV-1955 generates long-term, potent anti-Aß antibodies and cellular immune responses specific to foreign T-helper epitopes but not to self-Aß. CONCLUSIONS: This translational study demonstrates that a DNA-based epitope vaccine for AD could be appropriate for human clinical testing.
Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Vacinas contra Alzheimer/uso terapêutico , Ativação Linfocitária , Linfócitos T Auxiliares-Indutores/fisiologia , Peptídeos beta-Amiloides/imunologia , Animais , Anticorpos/sangue , Anticorpos/imunologia , Linhagem Celular Tumoral , Relação Dose-Resposta Imunológica , Epitopos de Linfócito T , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Estudos Longitudinais , Macaca mulatta , Masculino , Placa Amiloide/imunologia , Distribuição Aleatória , Fatores de Tempo , Pesquisa Translacional Biomédica , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêuticoRESUMO
OBJECTIVES: We report a multicenter experience with simultaneous right ventricular outflow tract (RVOT) stenting and transcatheter pulmonary valve implantation using the Melody valve (Medtronic). BACKGROUND: Prestenting the RVOT before Melody valve implantation is now the standard of care. Prestenting is usually performed as a separate step. The "one-step" technique for simultaneous landing zone stenting and Melody delivery was previously reported using only Max LD stents (Medtronic). We report a multicenter experience of simultaneous stenting and Melody implantation using multiple stent types in combination. METHODS: This retrospective cohort study includes 33 patients from 3 centers who underwent simultaneous stenting and Melody valve implantation between 2017 and 2020. Key variables were compared with 31 patients from the same centers who underwent standard (non-simultaneous) prestenting followed by Melody implantation during the same time frame. RESULTS: The 2 groups were similar in terms of age, weight, sex, and total procedure time. The 2 groups had similar clinical results and safety profiles, with no difference between the postimplantation right ventricle (RV) to pulmonary artery systolic pressure gradient, RV to aortic pressure ratio, and complication rate. The simultaneous group had lower radiation exposure as measured by dose area product. Up to 3 stents were safely placed simultaneously with a Melody valve. CONCLUSIONS: Simultaneous RVOT stenting and Melody valve implantation can safely be used to place up to 3 stents outside a Melody valve. This approach can simplify the catheterization procedure and potentially reduce radiation dose.
Assuntos
Valva Pulmonar , Catéteres , Ventrículos do Coração , Humanos , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/cirurgia , Estudos Retrospectivos , StentsRESUMO
This study examined perceived social support among children of parents diagnosed with cancer. Twenty-nine participants, ages 18-38, who had been children when one of their parents was diagnosed with cancer provided demographic information and participated in an interview about the impact of their parent's illness on their lives. Five common themes characterized participants' perceived social support received during their parent's illness: (a) listening and understanding; (b) encouragement and reassurance; (c) tangible assistance; (d) communication about cancer and treatment; and (e) engaging in normal life experiences. Depending on the circumstances, however, a given type of social support was perceived to be helpful to some, while perceived by others as ineffective or detrimental. Differences in respondents' perceptions of the effects of specific forms of received social support speak to the need for individualized support for children of cancer patients based upon each child's specific needs and circumstances.
Assuntos
Filho de Pais com Deficiência/psicologia , Julgamento , Neoplasias/psicologia , Relações Pais-Filho , Papel do Doente , Apoio Social , Adaptação Psicológica , Adolescente , Adulto , Criança , Comunicação , Comportamento de Ajuda , Humanos , Individualidade , Entrevista Psicológica , Acontecimentos que Mudam a Vida , Satisfação Pessoal , Inventário de Personalidade , Fatores Socioeconômicos , Adulto JovemRESUMO
Although ß-amyloid (Aß) may be the primary driver of Alzheimer's disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aß and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aß (AV-1959R), Tau (AV-1980R) or Aß/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with Advax(CpG), delta inulin, Alhydrogel(®), Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in Advax(CpG) induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with Advax(CpG) induced robust antibody responses against various forms of both, Aß and tau pathological molecules. While anti-Aß antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with Advax(CpG) adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials.
Assuntos
Doença de Alzheimer/imunologia , Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Formação de Anticorpos/imunologia , Proteínas tau/imunologia , Adjuvantes Imunológicos/uso terapêutico , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Vacinas contra Alzheimer/uso terapêutico , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Epitopos de Linfócito B/imunologia , Feminino , Humanos , Imunização/métodos , Inulina/análogos & derivados , Inulina/imunologia , Camundongos Endogâmicos C57BLRESUMO
DNA vaccines promote immune system activation in small animals and exhibit certain advantages when compared to conventional recombinant protein vaccines. However in clinical trials DNA vaccines are less effective in inducing potent immune responses due to the low delivery efficiency and expression of antigens. Currently, various delivery devices such as gene-guns, bioinjectors and electroporation systems are being used in order to increase the potency of DNA vaccines. However, the optimal delivery parameters are required and must be carefully set to obtain the highest levels of gene expression and strong immune responses in humans. The focus of this study was to optimize electroporation settings (voltage, pulse length, pulse intervals, and number of pulses), as well as the route of administration (intradermal vs. intramuscular) and dosage of the DNA epitope vaccine, AV-1959D, delivered by the BTX AgilePulse(TM) system. As a result, we have chosen the optimal settings for electroporation delivery using different routes of immunization with this vaccine, generating (i) robust antibody production to the B cell epitope (a small peptide, derived from ß-amyloid), and (ii) strong cellular immune responses to Th epitopes (a small synthetic peptide and eleven peptides from various pathogens) incorporated into DNA vaccine platform.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Eletroporação/instrumentação , Vacinação/métodos , Vacinas de DNA/administração & dosagem , Animais , Anticorpos/imunologia , Proliferação de Células , Citocinas/imunologia , Epitopos de Linfócito B/imunologia , Feminino , Imunidade Celular , Injeções Intradérmicas , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos C57BL , Plasmídeos , Proteínas Recombinantes/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
It is believed that primary tumor resection modulates host-tumor immune interaction, but this has not been characterized in a stringent breast cancer tumor model. This report, using the 4T1 murine mammary tumor model, characterizes for the first time the dynamic longitudinal changes in immunosuppressive and effector components of the immune system after resection of an established orthotopic primary tumor with a defined natural history of developing lung metastases. More specifically, we analyzed changes of absolute numbers and frequencies of MDSC, regulatory T cells (Treg), as well as activated CD4 and CD8 positive T cells in spleens and, in some studies, lungs of 4T1 tumor-bearing mice and mice after primary tumor resection. Importantly, using mathematical analyses we established that primary resection of an orthotopic tumor had created a "window of opportunity" with decreased tumor-associated immune suppression that existed for approximately 10 days. Although tumor resection did slightly prolong survival, it did not affect the ultimate development of metastatic disease since animals with resected tumors or intact primary tumors eventually died by day 47 and 43, respectively. This window of opportunity likely occurs in humans providing a rationale and parameters for integration and testing of immunotherapeutic strategies in this critical "window of opportunity" to combat the development of metastatic disease.
Assuntos
Imunoterapia , Neoplasias Mamárias Experimentais/cirurgia , Neoplasias Mamárias Experimentais/terapia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Mamárias Experimentais/imunologia , CamundongosRESUMO
Immunotherapeutic approaches reducing α-synuclein deposits may provide therapeutic benefit for Dementia with Lewy Bodies (DLB). Immunization with full-length human α-synuclein (hα-Syn) protein in a Parkinson's disease mouse model decreased the accumulation of the aggregated forms of this protein in neurons and reduced neurodegeneration. To enhance the immunogenicity of candidate vaccines and to avoid the risk of autoreactive anti-hα-Syn T-helper (Th) cell responses, we generated three peptide-based epitope vaccines composed of different B-cell epitopes of hα-Syn fused with a "non-self" Th epitope from tetanus toxin (P30). Immunization of mice with these epitope vaccines produced high titers of anti-hα-Syn antibodies that bound to Lewy bodies (LBs) and Lewy neurites (LNs) in brain tissue from DLB cases and induced robust Th cell responses to P30, but not to hα-Syn. Further development of these first generation epitope vaccines may facilitate induction of anti-hα-Syn immunotherapy without producing potentially harmful autoreactive Th cell responses.
Assuntos
Epitopos de Linfócito B/imunologia , Vacinas/imunologia , alfa-Sinucleína/imunologia , Animais , Formação de Anticorpos , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Epitopos de Linfócito B/genética , Estudos de Viabilidade , Feminino , Humanos , Corpos de Lewy/imunologia , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/imunologia , Doença por Corpos de Lewy/patologia , Camundongos , Neuritos/imunologia , Neuritos/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Toxina Tetânica/genética , Vacinação , Vacinas/genética , alfa-Sinucleína/genéticaRESUMO
Novel dual vaccine, WSN-Aß(1-10), based on the recombinant influenza virus, expressing immunodominant B-cell epitope of ß-amyloid, simultaneously induced therapeutically potent anti-Aß and anti-influenza antibodies. In this study we showed that boosting of WSN-WT primed mice with WSN-Aß(1-10) enhances anti-viral, but fails to induce anti-Aß antibody responses. This inhibition is associated with expression of Aß(1-10) within the context of an inactivated influenza virus vaccine. These results demonstrate that the use of an inactivated influenza virus as a carrier for AD vaccine may not be applicable due to the possible inhibition of anti-Aß antibody response in individuals previously vaccinated or infected with influenza.
Assuntos
Doença de Alzheimer , Vacinas contra Alzheimer/uso terapêutico , Peptídeos beta-Amiloides/imunologia , Influenza Humana/imunologia , Linfócitos/imunologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/imunologia , Doença de Alzheimer/prevenção & controle , Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/toxicidade , Análise de Variância , Animais , Anticorpos/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Testes de Inibição da Hemaglutinação , Humanos , Influenza Humana/virologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T ReguladoresRESUMO
We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope vaccine comprising three copies of a short amyloid-ß (Aß) B cell epitope, Aß 11 fused with the foreign promiscuous Th epitope, PADRE (p3Aß 11-PADRE) was immunogenic in mice. However, since DNA vaccines exhibit poor immunogenicity in large animals and humans, in this study, we sought to improve the immunogenicity of p3Aß 11-PADRE by modifying this vaccine to express protein 3Aß 11-PADRE with a free N-terminal aspartic acid fused with eight additional promiscuous Th epitopes. Generated pN-3Aß 11-PADRE-Thep vaccine has been designated as AV-1955. We also delivered this vaccine using the TriGrid electroporation system to improve the efficiency of DNA transfection. This third-generation DNA epitope vaccine was evaluated for immunogenicity in rabbits in comparison to the parent construct p3Aß 11-PADRE. AV-1955 vaccination induced significantly stronger humoral immune responses in rabbits compared with p3Aß 11-PADRE vaccine. Anti-Aß 11 antibodies recognized all forms of human ß-amyloid peptide (monomers, oligomers and fibrils), bound to amyloid plaques in brain sections from an AD case and reduced oligomer- and fibril-mediated cytotoxicity ex vivo. These findings suggest that AV-1955 could represent an effective DNA epitope vaccine for AD therapy, pending safety and efficacy studies that are currently being conducted in Rhesus monkeys.