RESUMEN
BACKGROUND: We conducted a systematic review to assess the safety and efficacy of Aluminum potassium sulfate and tannic acid (ALTA) sclerotherapy for the treatment of hemorrhoidal disease. METHODS: Our study was conducted in accordance with the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-analyses) 2020. Primary endpoints included overall recurrence and type of recurrence while secondary endpoints included postoperative complications, reintervention, presence of rectal ulcer, rectal stricture, defecation abnormalities and perianal abscess. Α regression analysis, where the percentage of patients with grade II, III and IV hemorrhoidal disease was used as a covariate, was also performed. RESULTS: Twelve studies with 4249 patients met all the inclusion criteria and were eventually included. The crude and pooled estimates of the overall recurrence and complications by the end of follow-up were 10% (95% CI, 6.52%-14.08%) and 5.20% (95% CI, 2.59%-8.52%), respectively. Regression analysis displayed no correlation between recurrence and the grade of hemorrhoid disease II, ß= -0.0012 (95% CI, -0.0074 to 0.0049) (p = .64), grade III ß= -0.0006 (95% CI, -0.0056 to 0.0045) (p = .79) and grade IV ß = 0.0025 (95% CI, -0.0075 to 0.0124). However, a trend suggestive of increased recurrence was observed in patient populations with a higher proportion of grade IV disease. CONCLUSION: ALTA sclerotherapy may be a safe and viable alternative for patients with hemorrhoidal disease. Long-term follow-up and high-quality randomized controlled trials will help define the place of ALTA sclerotherapy in the armamentarium of treatment of hemorrhoids.
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Compuestos de Alumbre , Hemorroides , Soluciones Esclerosantes , Escleroterapia , Taninos , Humanos , Hemorroides/terapia , Escleroterapia/métodos , Taninos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Soluciones Esclerosantes/uso terapéutico , Resultado del Tratamiento , Recurrencia , PolifenolesRESUMEN
OBJECTIVES: Spondyloarthritis (SpA) is known as series of immune-mediated inflammatory disease of the axial and peripheral joints. Human leucocyte antigen (HLA)-B27 is a genetic risk factor for SpA. Recent evidence suggests that the interleukin -17 (IL17) axis strongly contributes to SpA. This study aimed to assess the efficacy of an IL17A peptide-based vaccine on SpA manifestations in model rats. METHODS: HLA-B27/human ß2-microglobulin (hß2M) transgenic rats were immunised with heat-inactivated Mycobacterium tuberculosis (MT) to develop spondylitis and arthritis as an experimental SpA model after immunisation with a keyhole limpet hemocyanin-conjugated IL17A peptide-based vaccine with an alum adjuvant three times. The IL17A antibody titre was assessed using ELISA, and arthritis score and joint thickness were monitored two times a week. Enzyme-linked immunospot (ELISpot) assays for IL4- and interferon-γ-secreting splenocytes were conducted to evaluate IL17A-specific T cell activation. We also evaluated the effect of IL17A vaccine in SpA therapeutic model. RESULTS: The IL17A peptide-based vaccine with alum adjuvant successfully induced antibody production and suppressed the arthritis score and joint thickness. X-ray and histological analyses showed that enthesitis, bone destruction and new bone formation were inhibited by the IL17A vaccine. The ELISpot assay showed that the IL17A peptide-based vaccine did not elicit any IL17A-reactive T cell responses. IL17A vaccine tends to mitigate, but not significant, in SpA treatment model. These data showed that the peptide-based vaccine targeting IL17A alleviated the SpA phenotype in a heat-inactivated MT-induced SpA model in HLA-B27/hß2M transgenic rats. CONCLUSIONS: IL17A peptide-based vaccine may be a therapeutic option for SpA treatment.
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Antígeno HLA-B27 , Espondiloartritis , Humanos , Ratas , Animales , Ratas Transgénicas , Antígeno HLA-B27/genética , Espondiloartritis/tratamiento farmacológico , Compuestos de Alumbre/uso terapéutico , Interleucina-17RESUMEN
BACKGROUND: Aluminum potassium sulfate and tannic acid sclerotherapy for hemorrhoids produced almost the same effects as excisional hemorrhoidectomy. However, its long-term effectiveness remains unknown. OBJECTIVE: The purpose of this study was to investigate the long-term results of sclerotherapy using aluminum potassium sulfate and tannic acid for treating prolapsed hemorrhoids. DESIGN: This was a retrospective review of a single-institution experience. SETTINGS: This study was conducted within a coloproctology unit at a community-based hospital. PATIENTS: In total, 1180 patients with grade II to IV hemorrhoids treated with injection sclerotherapy were enrolled. MAIN OUTCOME MEASURES: Efficacy measures included cumulative recurrence rates and postoperative complications. RESULTS: Recurrence rates at 3, 6, and 9 years were 7.4%, 27.2%, and 47.5%. Postoperative complications included fever ≥38°C in 16 (1.4%) patients, rectal ulcer in 10 (0.9%) patients, rectal stricture in 5 (0.4%) patients, and perianal abscess in 4 (0.3%) patients. LIMITATIONS: This was a retrospective, nonrandomized, single-center study. In addition, office visits after 3 years were optional and the number of follow-ups steadily decreased. CONCLUSIONS: Sclerotherapy using aluminum potassium sulfate and tannic acid offers reasonable long-term results and is associated with low complication rates. Therefore, it seems to be an attractive alternative for patients with prolapsed hemorrhoids. See Video Abstract at http://links.lww.com/DCR/B733.RESULTADOS A LARGO PLAZO DE LA ESCLEROTERAPIA CON SULFATO DE ALUMINIO Y POTASIO, Y ÁCIDO TÁNICO PARA LAS HEMORROIDES PROLAPSADAS: ESTUDIO OBSERVACIONAL DE UN SOLO CENTRO. ANTECEDENTES: La escleroterapia con sulfato de aluminio y potasio, y ácido tánico para las hemorroides produjo casi los mismos efectos que la hemorroidectomía por escisión. Sin embargo, se desconoce su eficacia a largo plazo. OBJETIVO: El propósito de este estudio fue investigar los resultados a largo plazo de la escleroterapia con sulfato de aluminio y potasio, y ácido tánico para tratar las hemorroides prolapsadas. DISEO: Revisión retrospectiva de la experiencia de una sola institución. ENTORNO CLINICO: Este estudio se realizó dentro de una unidad de coloproctología en un hospital comunitario. PACIENTES: En total, 1.180 pacientes fueron inscritos con hemorroides grado II a IV tratados con inyecciones esclerosantes. PRINCIPALES MEDIDAS DE VALORACION: Las medidas de eficacia incluyeron tasas acumulativas de recurrencia y complicaciones posoperatorias. RESULTADOS: La tasa de recurrencia a los 3, 6 y 9 años fue del 7,4%, 27,2% y 47,5%, respectivamente. Las complicaciones posoperatorias incluyeron fiebre ≥ 38 grados Celsius en 16 pacientes (1,4%), úlcera rectal en 10 (0,9%), estenosis rectal en 5 (0,4%) y absceso perianal en 4 (0,3%) pacientes. LIMITACIONES: Este fue un estudio retrospectivo, no aleatorio, de un solo centro. Adicionalmente, las visitas al consultorio después de 3 años eran opcionales y el número de seguimientos disminuyó constantemente. CONCLUSIONES: La escleroterapia con sulfato de aluminio y potasio, y ácido tánico ofrece resultados razonables a largo plazo y está asociada con bajas tasas de complicaciones. Por tanto, parece ser una alternativa atractiva para pacientes con hemorroides prolapsadas. Consulte Video Resumen en http://links.lww.com/DCR/B733. (Traducción- Dr. Francisco M. Abarca-Rendon).
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Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Hemorroides/terapia , Escleroterapia , Taninos/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.
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Adyuvantes Inmunológicos/uso terapéutico , Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , Glicoproteína de la Espiga del Coronavirus/uso terapéutico , Adolescente , Adulto , Anciano , Compuestos de Alumbre/uso terapéutico , Bélgica , Brasil , Colombia , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oligodesoxirribonucleótidos/uso terapéutico , Filipinas , Multimerización de Proteína , Proteínas Recombinantes/uso terapéutico , Riesgo , SARS-CoV-2 , Sudáfrica , Eficacia de las Vacunas , Adulto JovenRESUMEN
Typically, the killed form of microorganisms in combination with alum does not produce strong cellular immune responses. A recent investigation has indicated the role of dopamine D2 receptor antagonists like metoclopramide in reducing the polarization of immune responses toward Th2 immunity. This study was performed to evaluate the effects of a combination of alum and metoclopramide on the induction of cellular and humoral immunity in response to a heat-killed preparation ofSalmonella typhimurium(HKST). Wistar rats were immunized with the HKST vaccine alone or in combination with alum, metoclopramide, or the alum-metoclopramide mixture twice with a two-week interval. Fourteen days after the last vaccination, immune responses against S. typhimurium and the protective potential of the vaccines were assessed. The combination of alum and metoclopramide as an adjuvant augmented the potential of the HKST vaccine to enhance lymphocyte proliferation, delayed-type hypersensitivity reaction, and antibody titer. These results were concurrent with the polarization of immune response towards the Th1 response and improving protective immunity against S. typhimurium. Overall, the combination of alum and metoclopramide as an adjuvant synergistically enhanced cellular and humoral immunity after immunization with the HKST vaccine.
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Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Inmunidad Celular/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Metoclopramida/uso terapéutico , Salmonella typhimurium/inmunología , Vacunas Tifoides-Paratifoides/uso terapéutico , Adyuvantes Inmunológicos/administración & dosificación , Compuestos de Alumbre/efectos adversos , Animales , Sinergismo Farmacológico , Hipersensibilidad Tardía/inmunología , Masculino , Metoclopramida/administración & dosificación , Ratas , Ratas Wistar , Salmonelosis Animal/inmunología , Salmonelosis Animal/prevención & control , Vacunas de Productos Inactivados/uso terapéuticoRESUMEN
The study sought to formulate and evaluate suppositories using a locally produced brand of alum (Aw) obtained from bauxite waste generated at Awaso bauxite mine in the Western-North region of Ghana, for use in the treatment of hemorrhoids. The suppositories were formulated using shea butter modified, respectively, with amounts of beeswax and theobroma oil. In another development, theobroma oil was modified with different concentrations of beeswax. Drug-base interactions were investigated using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy. The suppositories were prepared using the hot melt and trituration methods. Quality control checks were carried out on the formulations. The evaluated parameters included physical characteristics (texture, presence or absence of entrapped air, and contraction holes), weight uniformity, disintegration time, drug content, and in vitro release profile of the alum from the formulated suppositories. An in vivo analysis was carried out on the most suitable formulation to ascertain its efficacy on inflamed tissues using croton oil-induced rectal inflammation in a rat model. A critical examination of the ATR-FTIR spectra revealed no drug-base interactions. The suppository formulations passed all Pharmacopoeia stated tests. The in vivo study revealed the use of suppositories ameliorated the croton oil-induced hemorrhoid in the rectoanal region of the rats.
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Compuestos de Alumbre/uso terapéutico , Hemorroides/tratamiento farmacológico , Sulfatos/uso terapéutico , Compuestos de Alumbre/administración & dosificación , Óxido de Aluminio , Animales , Ghana , Humanos , Masculino , Minería , Ratas , Ratas Sprague-Dawley , Espectroscopía Infrarroja por Transformada de Fourier , Sulfatos/administración & dosificación , SupositoriosRESUMEN
ABSTRACT: Neonatal sepsis leads to significant morbidity and mortality with the highest risk of death occurring in preterm (<37 weeks) and low birth weight (<2,500âg) infants. The neonatal immune system is developmentally immature with well-described defects in innate and adaptive immune responses. Immune adjuvants used to enhance the vaccine response have emerged as potential therapeutic options, stimulating non-specific immunity and preventing sepsis mortality. Aluminum salts ("alum") have been used as immune adjuvants for over a century, but their mechanism of action remains poorly understood. This study aims to identify potential mechanisms by which pretreatment with alum induces host protective immunity to polymicrobial sepsis in neonatal mice. Utilizing genetic and cell-depletion studies, we demonstrate here that the prophylactic administration of aluminum adjuvants in neonatal mice improves sepsis survival via activation of the nucleotide oligomerization domain-like receptor family, pyrin-domain-containing 3 inflammasome and dendritic cell activation. Furthermore, this beneficial effect is dependent on myeloid, non-granulocytic Gr1-positive cells, and MyD88-signaling pathway activation. These findings suggest a promising therapeutic role for aluminum-based vaccine adjuvants to prevent development of neonatal sepsis and improve mortality in this highly vulnerable population.
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Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Inflamasomas/fisiología , Células Mieloides/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Sepsis Neonatal/tratamiento farmacológico , Sepsis Neonatal/mortalidad , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Femenino , Granulocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Tasa de SupervivenciaRESUMEN
Enhanced type 2 helper T (Th2) cell responses to inhaled harmless allergens are strongly associated with the development of allergic diseases. Antigen formulated with an appropriate adjuvant can elicit suitable systemic immunity to protect individuals from disease. Although much has been learned about Th1-favored immunomodulation of OK-432, a streptococcal preparation with antineoplastic activity, little is known about its adjuvant effect for allergic diseases. Herein, we demonstrate that OK-432 acts as an adjuvant to favor a systemic Th1 polarization with an elevation in interferon- (IFN-) γ and ovalbumin- (OVA-) immunoglobulin (Ig) G2a. Prior vaccination with OK-432 formulated against OVA attenuated lung eosinophilic inflammation and Th2 cytokine responses that were caused by challenging with OVA through the airway. This vaccination with OK-432 augmented the ratios of IFN-γ/interleukin- (IL-) 4 cytokine and IgG2a/IgG1 antibody compared to the formulation with Th2 adjuvant aluminum hydroxide (Alum) or antigen only. The results obtained in this study lead us to propose a potential novel adjuvant for clinical use such as prophylactic vaccination for pathogens and immunotherapy in atopic diseases.
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Adyuvantes Inmunológicos/uso terapéutico , Asma/tratamiento farmacológico , Inmunoterapia/métodos , Picibanil/uso terapéutico , Células TH1/inmunología , Células Th2/inmunología , Compuestos de Alumbre/uso terapéutico , Animales , Asma/inmunología , Diferenciación Celular , Modelos Animales de Enfermedad , Humanos , Inmunoglobulina G/sangre , Inmunomodulación , Interferón gamma/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
PURPOSE OF REVIEW: There are various specific therapeutic intervention available to treat hemorrhagic cystitis, once emergency treatment has been carried out. The lack of prospective studies, because of the relative rarity of this condition, makes it difficult to hierarchize the therapeutic sequence. The present review presents and summarizes the literature published on radiation-induced hemorrhagic cystitis from April 2015, date of a precedent exhaustive review, to March 2018. RECENT FINDINGS: During our period of interest, 13 clinical studies and two new clinical trials protocols were published. Most of the clinical studies were retrospective and presented data about hyperbaric oxygen (HBO) therapy, comforting its place as a well tolerated and effective first-line treatment. Other studies reported the outcomes of treatments with alum, formalin, silver nitrate, fulguration with laser or definitive surgery. SUMMARY: Although authors seem to agree that formalin and surgery have their role as effective but potentially morbid last-line treatments, there is no consensus on primary approach to management of radiation-induced hemorrhagic cystitis beyond symptomatic measures. Several treatments have proven excellent response rates and few side effects. The results of on-going prospective studies on mesenchymal stromal cells or tacrolimus instillations are awaited, but the main discriminating factor to choose between treatments remains local availability.
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Cistitis/terapia , Hemorragia/terapia , Oxigenoterapia Hiperbárica/métodos , Traumatismos por Radiación/terapia , Compuestos de Alumbre/uso terapéutico , Cistitis/epidemiología , Formaldehído/uso terapéutico , Hemorragia/epidemiología , Humanos , Nitrato de Plata/uso terapéuticoRESUMEN
Toxic effects of available therapeutics are major drawbacks for conventional management approaches in parasitic infections. Vaccines have provided a promising opportunity to obviate such unwanted complications. In present study, we examined immune augmenting capacities of an emerging adjuvant, Naltrexone, against Fasciola hepatica infection in BALB/c mice. Seventy BALB/c mice were divided into five experimental groups (14 mice per group) including 1- control (received PBS), 2- vaccine (immunized with F. hepatica E/S antigens), 3- Alum-vaccine (immunized with Alum adjuvant and E/S antigens), 4- NLT-vaccine (immunized with NLT adjuvant and E/S antigens), and 5- Alum-NLT-vaccine (immunized with mixed Alum-NLT adjuvant and E/S antigens). Lymphocyte stimulation index was assessed by MTT assay. Production of IFN-γ, IL-4, IgG2a and IgG1 was assessed by ELISA method. Results showed that NLT, either alone or in combination with alum, can induce immune response toward production of IFN-γ and IgG2a as representatives of Th1 immune response. Also, using this adjuvant in immunization experiment was associated with significantly high proliferative response of splenocytes/lymphocytes. Utilization of mixed Alum-NLT adjuvant revealed the highest protection rate (73.8%) in challenge test of mice infected with F. hepatica. These findings suggest the potential role of NLT as an effective adjuvant in induction of protective cellular and Th1 immune responses against fasciolosis.
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Adyuvantes Inmunológicos/uso terapéutico , Fasciola hepatica/inmunología , Fascioliasis/prevención & control , Naltrexona/uso terapéutico , Células TH1/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Compuestos de Alumbre/administración & dosificación , Compuestos de Alumbre/farmacología , Compuestos de Alumbre/uso terapéutico , Animales , Anticuerpos Antihelmínticos/sangre , Ensayo de Inmunoadsorción Enzimática , Fasciola hepatica/efectos de los fármacos , Fascioliasis/tratamiento farmacológico , Fascioliasis/inmunología , Femenino , Inmunidad Celular/efectos de los fármacos , Inmunización , Inmunoglobulina G/sangre , Interferón gamma/análisis , Interleucina-4/análisis , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Naltrexona/administración & dosificación , Naltrexona/farmacología , Distribución Aleatoria , Ovinos , Células TH1/efectos de los fármacos , Vacunas Virales/administración & dosificaciónRESUMEN
Survivin has received attention as a potential target for cancer immunotherapy because of its crucial role in oncogenesis. We undertook this study to evaluate the immunotherapeutic potential of combination of recombinant survivin along with adjuvant alum and immune modulator Mycobacterium indicus pranii (MIP). In vivo efficacy of the combination was studied in an invasive murine breast cancer model. Recombinant survivin protein was purified from Escherichia coli based expression system and characterized by western blotting. Purified survivin protein was combined with alum and MIP and was used for immunization of Balb/c mice. Antigen-primed animals were then challenged with syngeneic mammary tumor cells known as 4T-1. Balb/c mice spontaneously develop tumor when inoculated with 4T-1 cells. Antigen and adjuvant combination was immunogenic and significantly suppressed tumor growth in mice immunized with combination of recombinant survivin (10 µg), alum, and MIP. This is the first report that describes a combination immunotherapy approach using recombinant survivin, alum, and MIP in highly metastatic murine breast cancer model and holds promise for development of new biotherapeutics for cancer.
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Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Neoplasias de la Mama/prevención & control , Vacunas contra el Cáncer/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Proteínas Represoras/uso terapéutico , Animales , Neoplasias de la Mama/patología , Modelos Animales de Enfermedad , Femenino , Inmunización , Inmunoterapia , Ratones Endogámicos BALB C , Proteínas Recombinantes/uso terapéutico , SurvivinRESUMEN
The high mortality in neonatal sepsis has been related to both quantitative and qualitative differences in host protective immunity. Pretreatment strategies to prevent sepsis have received inadequate consideration, especially in the premature neonate, where outcomes from sepsis are so dismal. Aluminium salts-based adjuvants (alum) are used currently in many paediatric vaccines, but their use as an innate immune stimulant alone has not been well studied. We asked whether pretreatment with alum adjuvant alone could improve outcome and host innate immunity in neonatal mice given polymicrobial sepsis. Subcutaneous alum pretreatment improves survival to polymicrobial sepsis in both wild-type and T and B cell-deficient neonatal mice, but not in caspase-1/11 null mice. Moreover, alum increases peritoneal macrophage and neutrophil phagocytosis, and decreases bacterial colonization in the peritoneum. Bone marrow-derived neutrophils from alum-pretreated neonates produce more neutrophil extracellular traps (NETs) and exhibit increased expression of neutrophil elastase (NE) after in-vitro stimulation with phorbol esters. In addition, alum pretreatment increases bone marrow and splenic haematopoietic stem cell expansion following sepsis. Pretreatment of neonatal mice with an alum-based adjuvant can stimulate multiple innate immune cell functions and improve survival. These novel findings suggest a therapeutic pathway for the use of existing alum-based adjuvants for preventing sepsis in premature infants.
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Adyuvantes Inmunológicos , Compuestos de Alumbre/uso terapéutico , Vacunas Bacterianas/inmunología , Macrófagos Peritoneales/inmunología , Células Mieloides/fisiología , Neutrófilos/inmunología , Sepsis/inmunología , Animales , Animales Recién Nacidos , Linfocitos B/fisiología , Caspasa 1/genética , Caspasa 1/metabolismo , Caspasas/genética , Caspasas/metabolismo , Caspasas Iniciadoras , Autorrenovación de las Células , Modelos Animales de Enfermedad , Trampas Extracelulares/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis , Sepsis/prevención & control , Linfocitos T/fisiologíaRESUMEN
Adjuvants have been deliberately added to vaccines since the 1920's when alum was discovered to boost antibody responses, leading to better protection. The first adjuvants were discovered by accident and were used in the safer but less immunogenic subunit vaccines, supposedly by providing an antigen depot to extend antigen presentation. Since that time, much has been discovered about how these adjuvants impact cells at the tissue site to activate innate immune responses, mobilize dendritic cells and drive adaptive immunity. New approaches to vaccine construction for infectious diseases that have so far not been well addressed by conventional vaccines often attempt to induce antibodies, polyfunctional CD4+ T cells and CD8+ CTLs. The discovery of pattern recognition receptors and ligands that drive desired T cell responses has led to development of novel adjuvant strategies using immunomodulatory agents to direct appropriate immune responses.
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Adyuvantes Inmunológicos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Vacunas/inmunología , Inmunidad Adaptativa , Compuestos de Alumbre/uso terapéutico , Animales , Formación de Anticuerpos , Presentación de Antígeno , Humanos , Activación de LinfocitosRESUMEN
Adjuvants are included in sub-unit or recombinant vaccines to enhance the potency of poorly immunogenic antigens. Adjuvant discovery is as complex as it is a multidiscplinary intersection of formulation science, immunology, toxicology, and biology. Adjuvants such as alum, which have been in use for the past 90 years, have illustrated that adjuvant research is a methodical process. As science advances, new analytical tools are developed which allows us to delve deeper into the various mechanisms that generates a potent immune response. Additionally, these new techniques help the field learn about our existing vaccines and what makes them safe, and effective, allowing us to leverage that in the next generation of vaccines. Our goal in this chapter is to define the concept, need, and mechanism of adjuvants in the vaccine field while describing its history, present use, and future prospects. More details on individual adjuvants and their formulation, development, mechanism, and use will be covered in depth in the next chapters.
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Adyuvantes Inmunológicos , Compuestos de Alumbre , Vacunas , Adyuvantes Inmunológicos/historia , Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/historia , Compuestos de Alumbre/uso terapéutico , Animales , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Vacunas/historia , Vacunas/uso terapéuticoRESUMEN
This study introduces a flexible format for tolerogenic vaccination that incorporates IFN-ß and neuroantigen (NAg) in the Alum adjuvant. Tolerogenic vaccination required all three components, IFN-ß, NAg, and Alum, for inhibition of experimental autoimmune encephalomyelitis (EAE) and induction of tolerance. Vaccination with IFN-ß + NAg in Alum ameliorated NAg-specific sensitization and inhibited EAE in C57BL/6 mice in pretreatment and therapeutic regimens. Tolerance induction was specific for the tolerogenic vaccine Ag PLP178-191 or myelin oligodendrocyte glycoprotein (MOG)35-55 in proteolipid protein- and MOG-induced models of EAE, respectively, and was abrogated by pretreatment with a depleting anti-CD25 mAb. IFN-ß/Alum-based vaccination exhibited hallmarks of infectious tolerance, because IFN-ß + OVA in Alum-specific vaccination inhibited EAE elicited by OVA + MOG in CFA but not EAE elicited by MOG in CFA. IFN-ß + NAg in Alum vaccination elicited elevated numbers and percentages of FOXP3+ T cells in blood and secondary lymphoid organs in 2D2 MOG-specific transgenic mice, and repeated boosters facilitated generation of activated CD44high CD25+ regulatory T cell (Treg) populations. IFN-ß and MOG35-55 elicited suppressive FOXP3+ Tregs in vitro in the absence of Alum via a mechanism that was neutralized by anti-TGF-ß and that resulted in the induction of an effector CD69+ CTLA-4+ IFNAR+ FOXP3+ Treg subset. In vitro IFN-ß + MOG-induced Tregs inhibited EAE when transferred into actively challenged recipients. Unlike IFN-ß + NAg in Alum vaccines, vaccination with TGF-ß + MOG35-55 in Alum did not increase Treg percentages in vivo. Overall, this study indicates that IFN-ß + NAg in Alum vaccination elicits NAg-specific, suppressive CD25+ Tregs that inhibit CNS autoimmune disease. Thus, IFN-ß has the activity spectrum that drives selective responses of suppressive FOXP3+ Tregs.
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Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Encefalomielitis Autoinmune Experimental/terapia , Interferón beta/metabolismo , Esclerosis Múltiple/terapia , Proteína Proteolipídica de la Mielina/uso terapéutico , Glicoproteína Mielina-Oligodendrócito/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Linfocitos T Reguladores/inmunología , Vacunas/uso terapéutico , Animales , Efecto Espectador , Células Cultivadas , Factores de Transcripción Forkhead/metabolismo , Humanos , Tolerancia Inmunológica , Interferón beta/uso terapéutico , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína Proteolipídica de la Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/inmunologíaRESUMEN
A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Vacunas contra el SIDAS/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Vacunas Virales/uso terapéutico , Inmunidad Adaptativa/inmunología , Animales , Inmunidad Innata/inmunología , Inmunidad Mucosa , Inmunogenicidad Vacunal , Inmunoglobulina G/inmunología , Interleucina-17/inmunología , Linfocitos , Macaca mulatta , Glicoproteínas de Membrana/inmunología , Distribución Aleatoria , Transducción de Señal , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Transcriptoma , Proteínas del Envoltorio Viral/inmunología , Proteínas ras/inmunologíaRESUMEN
Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Vacunas contra el Cáncer/inmunología , Inmunoterapia/métodos , Lectinas Tipo C/uso terapéutico , Neoplasias/terapia , Oligodesoxirribonucleótidos/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Humanos , Inmunomodulación , Neoplasias/inmunología , VacunaciónRESUMEN
Over the past three decades there have been a number of clinical trials directed at interdicting the type 1 diabetes (T1D) disease process in an attempt to prevent the development of the disease in those at increased risk or to stabilize-potentially even reverse-the disease in people with T1D, usually of recent onset. Unfortunately, to date there has been no prevention trial that has resulted in delay or prevention of T1D. And, trials in people with T1D have had mixed results with some showing promise with at least transient improvement in ß-cell function compared with randomized control groups, while others have failed to slow the decline in ß-cell function when compared with placebo. This Perspective will assess the past and present challenges in this effort and provide an outline for potential future opportunities.
Asunto(s)
Diabetes Mellitus Tipo 1/prevención & control , Compuestos de Alumbre/uso terapéutico , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Vacuna BCG/uso terapéutico , Chaperonina 60/uso terapéutico , Diabetes Mellitus Tipo 1/fisiopatología , Predicción , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Hipoglucemiantes/uso terapéutico , Células Secretoras de Insulina/fisiología , Interleucina-2/uso terapéutico , Ratones , Fragmentos de Péptidos/uso terapéutico , Proyectos Piloto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Resultado del TratamientoRESUMEN
STATEMENT OF PROBLEM: A high percentage of fixed prosthodontic restorations require a subgingival margin placement, which requires the practice of gingival displacement or a deflection procedure to replicate the margins in impression. PURPOSE: The purpose of this study was to learn the different gingival displacement techniques that are currently used by dentists in their practice and to compare the current concepts of gingival displacement with previously published articles. MATERIALS AND METHODS: A survey of questions pertaining to gingival deflection methods was distributed as part of continuing education (CE) course material to dentists attending CE meetings in 7 states in the U.S. and 1 Canadian province. Question topics included initial patient assessment procedures, gingival displacement methods, dentist's knowledge and assessment of systemic manifestations, and brand names of materials used. RESULTS: Ninety-four percent of the participants were general practitioners with 24.11 ± 12.5 years of experience. Ninety-two percent used gingival displacement cords, while 20.2% used a soft tissue laser and 32% used electrosurgery as an adjunct. Sixty percent of the dentists used displacement cords impregnated with a medicament. Of the preimpregnated cords, 29% were impregnated with epinephrine, 13% with aluminum chloride, and 18% with aluminum potassium sulfate. CONCLUSION: The study showed a steady decrease compared with results of previously published articles in the use of epinephrine as a gingival deflection medicament.
Asunto(s)
Técnicas de Retracción Gingival , Compuestos de Alumbre/uso terapéutico , Cloruro de Aluminio , Compuestos de Aluminio/uso terapéutico , Ansiedad/psicología , Arritmias Cardíacas/inducido químicamente , Astringentes/uso terapéutico , Presión Sanguínea/fisiología , Cloruros/uso terapéutico , Competencia Clínica , Electrocirugia/métodos , Epinefrina/efectos adversos , Epinefrina/uso terapéutico , Compuestos Férricos/uso terapéutico , Odontología General/educación , Técnicas de Retracción Gingival/instrumentación , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/inducido químicamente , Terapia por Láser/métodos , Anamnesis , Planificación de Atención al Paciente , Vasoconstrictores/efectos adversos , Vasoconstrictores/uso terapéuticoRESUMEN
OBJECTIVES: To review the state of the art and assess future potential in the use of inorganic particulates as vaccine adjuvants. KEY FINDINGS: An adjuvant is an entity added to a vaccine formulation to ensure that robust immunity to the antigen is inculcated. The inclusion of an adjuvant is typically vital for the efficacy of vaccines using inactivated organisms, subunit and DNA antigens. With increasing research efforts being focused on subunit and DNA antigens because of their improved safety profiles, the development of appropriate adjuvants is becoming ever more crucial. Despite this, very few adjuvants are licensed for use in humans (four by the FDA, five by the European Medicines Agency). The most widely used adjuvant, alum, has been used for nearly 90 years, yet its mechanism of action remains poorly understood. In addition, while alum produces a powerful antibody Th2 response, it does not provoke the cellular immune response required for the elimination of intracellular infections or cancers. New adjuvants are therefore needed, and inorganic systems have attracted much attention in this regard. SUMMARY: In this review, the inorganic adjuvants currently in use are considered, and the efforts made to date to understand their mechanisms of action are summarised. We then move on to survey the literature on inorganic particulate adjuvants, focusing on the most interesting recent developments in this area and their future potential.