RESUMO
BACKGROUND: SARS-CoV2 induces flu-like symptoms that can rapidly progress to severe acute lung injury and even death. The virus also invades the central nervous system (CNS), causing neuroinflammation and death from central failure. Intravenous (IV) or oral dexamethasone (DXM) reduced 28 d mortality in patients who required supplemental oxygen compared to those who received conventional care alone. Through these routes, DMX fails to reach therapeutic levels in the CNS. In contrast, the intranasal (IN) route produces therapeutic levels of DXM in the CNS, even at low doses, with similar systemic bioavailability. AIMS: To compare IN vs. IV DXM treatment in hospitalized patients with COVID-19. METHODS: A controlled, multicenter, open-label trial. Patients with COVID-19 (69) were randomly assigned to receive IN-DXM (0.12 mg/kg for three days, followed by 0.6 mg/kg for up to seven days) or IV-DXM (6 mg/d for 10 d). The primary outcome was clinical improvement, as defined by the National Early Warning Score (NEWS) ordinal scale. The secondary outcome was death at 28 d between IV and IN patients. Effects of both treatments on biochemical and immunoinflammatory profiles were also recorded. RESULTS: Initially, no significant differences in clinical severity, biometrics, and immunoinflammatory parameters were found between both groups. The NEWS-2 score was reduced, in 23 IN-DXM treated patients, with no significant variations in the 46 IV-DXM treated ones. Ten IV-DXM-treated patients and only one IN-DXM patient died. CONCLUSIONS: IN-DMX reduced NEWS-2 and mortality more efficiently than IV-DXM, suggesting that IN is a more efficient route of DXM administration.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , RNA Viral , Tratamento Farmacológico da COVID-19 , Dexametasona/uso terapêuticoRESUMO
Several COVID-19 vaccines use adenovirus vectors to deliver the SARS-CoV-2 spike (S) protein. Immunization with these vaccines promotes immunity against the S protein, but against also the adenovirus itself. This could interfere with the entry of the vaccine into the cell, reducing its efficacy. Herein, we evaluate the efficiency of an adenovirus-vectored vaccine (chimpanzee ChAdOx1 adenovirus, AZD1222) in boosting the specific immunity compared to that induced by a recombinant receptor-binding domain (RBD)-based vaccine without viral vector. Mice immunized with the AZD1222 human vaccine were given a booster 6 months later, with either the homologous vaccine or a recombinant vaccine based on RBD of the delta variant, which was prevalent at the start of this study. A significant increase in anti-RBD antibody levels was observed in rRBD-boosted mice (31-61%) compared to those receiving two doses of AZD1222 (0%). Significantly higher rates of PepMix™- or RBD-elicited proliferation were also observed in IFNγ-producing CD4 and CD8 cells from mice boosted with one or two doses of RBD, respectively. The lower efficiency of the ChAdOx1-S vaccine in boosting specific immunity could be the result of a pre-existing anti-vector immunity, induced by increased levels of anti-adenovirus antibodies found both in mice and humans. Taken together, these results point to the importance of avoiding the recurrent use of the same adenovirus vector in individuals with immunity and memory against them. It also illustrates the disadvantages of ChAdOx1 adenovirus-vectored vaccine with respect to recombinant protein vaccines, which can be used without restriction in vaccine-booster programs. KEY POINTS: ⢠ChAdOx1 adenovirus vaccine (AZD1222) may not be effective in boosting anti-SARS-CoV-2 immunity ⢠A recombinant RBD protein vaccine is effective in boosting anti-SARS-CoV-2 immunity in mice ⢠Antibodies elicited by the rRBD-delta vaccine persisted for up to 3 months in mice.
Assuntos
Vacinas contra Adenovirus , COVID-19 , Vacinas , Humanos , Animais , Camundongos , Pan troglodytes , ChAdOx1 nCoV-19 , Vacinas contra COVID-19/genética , SARS-CoV-2 , COVID-19/prevenção & controle , Adenoviridae/genética , Vacinação , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
The rapid spread of COVID-19 on all continents and the mortality induced by SARS-CoV-2 virus, the cause of the pandemic coronavirus disease 2019 (COVID-19) has motivated an unprecedented effort for vaccine development. Inactivated viruses as well as vaccines focused on the partial or total sequence of the Spike protein using different novel platforms such us RNA, DNA, proteins, and non-replicating viral vectors have been developed. The high global need for vaccines, now and in the future, and the emergence of new variants of concern still requires development of accessible vaccines that can be adapted according to the most prevalent variants in the respective regions. Here, we describe the immunogenic properties of a group of theoretically predicted RBD peptides to be used as the first step towards the development of an effective, safe and low-cost epitope-focused vaccine. One of the tested peptides named P5, proved to be safe and immunogenic. Subcutaneous administration of the peptide, formulated with alumina, induced high levels of specific IgG antibodies in mice and hamsters, as well as an increase of IFN-γ expression by CD8+ T cells in C57 and BALB/c mice upon in vitro stimulation with P5. Neutralizing titers of anti-P5 antibodies, however, were disappointingly low, a deficiency that we will attempt to resolve by the inclusion of additional immunogenic epitopes to P5. The safety and immunogenicity data reported in this study support the use of this peptide as a starting point for the design of an epitope restricted vaccine.
Assuntos
COVID-19 , Vacinas Virais , Cricetinae , Humanos , Camundongos , Animais , SARS-CoV-2 , Epitopos , Glicoproteína da Espícula de Coronavírus/genética , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Anticorpos Antivirais , Imunoglobulina G , Peptídeos , RNA , Óxido de Alumínio , Anticorpos NeutralizantesRESUMO
BACKGROUND: By end December of 2021, COVID-19 has infected around 276 million individuals and caused over 5 million deaths worldwide. Infection results in dysregulated systemic inflammation, multi-organ dysfunction, and critical illness. Cells of the central nervous system are also affected, triggering an uncontrolled neuroinflammatory response. Low doses of glucocorticoids, administered orally or intravenously, reduce mortality among moderate and severe COVID-19 patients. However, low doses administered by these routes do not reach therapeutic levels in the CNS. In contrast, intranasally administered dexamethasone can result in therapeutic doses in the CNS even at low doses. METHODS: This is an approved open-label, multicenter, randomized controlled trial to compare the effectiveness of intranasal versus intravenous dexamethasone administered in low doses to moderate and severe COVID-19 adult patients. The protocol is conducted in five health institutions in Mexico City. A total of 120 patients will be randomized into two groups (intravenous vs. intranasal) at a 1:1 ratio. Both groups will be treated with the corresponding dexamethasone scheme for 10 days. The primary outcome of the study will be clinical improvement, defined as a statistically significant reduction in the NEWS-2 score of patients with intranasal versus intravenous dexamethasone administration. The secondary outcome will be the reduction in mortality during hospitalization. CONCLUSIONS: This protocol is currently in progress to improve the efficacy of the standard therapeutic dexamethasone regimen for moderate and severe COVID-19 patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04513184 . Registered November 12, 2020. Approved by La Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS) with identification number DI/20/407/04/36. People are currently being recruited.
Assuntos
Tratamento Farmacológico da COVID-19 , Dexametasona/efeitos adversos , Humanos , Inflamação , Doenças Neuroinflamatórias , SARS-CoV-2 , Resultado do TratamentoRESUMO
Sea cucumber body wall contains several naturally occurring bioactive components that possess health-promoting properties. Isostichopus badionotus from Yucatan, Mexico is heavily fished, but little is known about its bioactive constituents. We previously established that I. badionotus meal had potent anti-inflammatory properties in vivo. We have now screened some of its constituents for anti-inflammatory activity in vitro. Glycosaminoglycan and soluble protein preparations reduced 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory responses in HaCaT cells while an ethanol extract had a limited effect. The primary glycosaminoglycan (fucosylated chondroitin sulfate; FCS) was purified and tested for anti-inflammatory activity in vivo. FCS modulated the expression of critical genes, including NF-ĸB, TNFα, iNOS, and COX-2, and attenuated inflammation and tissue damage caused by TPA in a mouse ear inflammation model. It also mitigated colonic colitis caused in mice by dextran sodium sulfate. FCS from I. badionotus of the Yucatan Peninsula thus had strong anti-inflammatory properties in vivo.
Assuntos
Anti-Inflamatórios , Sulfatos de Condroitina/isolamento & purificação , Sulfatos de Condroitina/farmacologia , Glicosaminoglicanos/isolamento & purificação , Glicosaminoglicanos/farmacologia , Otite/tratamento farmacológico , Pepinos-do-Mar/química , Extratos de Tecidos/isolamento & purificação , Extratos de Tecidos/farmacologia , Animais , Sulfatos de Condroitina/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Células HaCaT , Humanos , Técnicas In Vitro , México , Camundongos , Otite/induzido quimicamente , Acetato de Tetradecanoilforbol/efeitos adversosRESUMO
Sleep is considered an important modulator of the immune response. Thus, a lack of sleep can weaken immunity, increasing organism susceptibility to infection. For instance, shorter sleep durations are associated with a rise in suffering from the common cold. The function of sleep in altering immune responses must be determined to understand how sleep deprivation increases the susceptibility to viral, bacterial, and parasitic infections. There are several explanations for greater susceptibility to infections after reduced sleep, such as impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes, which have been observed during partial sleep deprivation. Also, steroid hormones, in addition to regulating sexual behavior, influence sleep. Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections. This review discusses the evidence on the bidirectional effects of the immune response against viral, bacterial, and parasitic infections on sleep patterns and how the lack of sleep affects the immune response against such agents. Because sleep is essential in the maintenance of homeostasis, these situations must be adapted to elicit changes in sleep patterns and other physiological parameters during the immune response to infections to which the organism is continuously exposed.
Assuntos
Resistência à Doença , Imunidade , Infecções/etiologia , Sono , Animais , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Sistema Imunitário/fisiologia , Infecções/metabolismoRESUMO
Major depressive disorder patients present chronic stress and decreased immunity. The Wistar-Kyoto rat (WKY) is a strain in which the hypothalamic-pituitary-adrenal axis is overactivated. To determine whether chronic stress induces changes in corticosterone levels and splenic lymphoid tissue, 9-week-old male rats were subject to restraint stress (3 h daily), chemical stress (hydrocortisone treatment, 50 mg/Kg weight), mixed stress (restraint plus hydrocortisone), or control treatment (without stress) for 1, 4, and 7 weeks. The serum corticosterone levels by RIA and spleens morphology were analyzed. Corticosterone levels as did the structure, size of the follicles and morphology of the parenchyma (increase in red pulp) in the spleen, varied depending on time and type of stressor. These changes indicate that chronic stress alters the immune response in the spleen in WKY rats by inducing morphological changes, explaining in part the impaired immunity that develops in organisms that are exposed to chronic stress.
Assuntos
Corticosterona/sangue , Transtorno Depressivo Maior/metabolismo , Estresse Fisiológico , Animais , Transtorno Depressivo Maior/fisiopatologia , Humanos , Hidrocortisona/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Ratos , Ratos Endogâmicos WKY , Baço/metabolismo , Baço/patologiaRESUMO
INTRODUCTION: Human Limbal Epithelial Cells (hLEC) are stem cells that give rise to corneal epithelium. After corneal damage, hLEC produce large amounts of IL-8 and IL-6, inducing inflammation in cornea and conjunctiva. Despite inflammation is necessary to repair the ocular surface since this process may be potentially harmful and could lead to corneal opacity. Ophthalmic infectious diseases have been treated with human dialyzable leukocyte extracts (hDLE). Clinical observations in hDLE-treated patients, have suggested an apparent control of ocular inflammatory injuries, without changes in the re-epithelialization process. OBJECTIVE: To determine the inflammatory cytokine profile in supernatants (SN) of hLEC cultured with hDLE. METHODS: hLEC were obtained from cadaver donors. hDLE were added to the hLEC cultures, and SN were collected at different times (1h, 3h, 6h, and 24h). IL-1?, IL 6, IL-8, IL-12p70 and TNF-? were measured in SN with cytometric bead arrays. RESULTS: The majority of isolated cells were CK19+/vimentin+/p63+, indicating that cultured-cells were limbal epithelial stem cells. Limbal cells responded to hDLE by diminishing the secretion of IL-8 and IL-6. Secretion of IL-8 and IL-6 was down-regulated significantly at 24h of culture with hDLE. Interestingly, hDLE did not induce secretion of IL-1 ?, TNF-?, and IL-12p70 in hLEC at any evaluated times. CONCLUSIONS: hDLE down-regulates secretion of IL-8 and IL-6 without induction of IL-1 ?, TNF-a, and IL-12p70 in hLEC. Our results provide a basis to understand some clinical effects, related to control ocular inflammation, that have been observed in patients treated with hDLE.
Assuntos
Interleucina-8 , Fator de Transferência , Células Cultivadas , Córnea , Regulação para Baixo , Células Epiteliais , Humanos , Interleucina-6RESUMO
Recombinant functional Taenia solium calreticulin (rTsCRT) confers different degrees of protection in the experimental model of intestinal taeniosis in hamsters. The aim of this study was to evaluate the immune response induced after oral or systemic immunization with an electroeluted rTsCRT in BALB/c mice. Oral immunization elicited high fecal IgA and the production of IL-4 and IL-5 by mesenteric lymph node cells after in vitro stimulation with rTSCRT, indicating a Th2 response. Mice subcutaneously immunized produced high amounts of serum IgG, being IgG1 (Th2-related) the predominant isotype, while in vitro stimulated spleen cells synthesized IL-4, IL-5 and also IFN-γ, indicating a mixed Th1/Th2 cellular response after systemic immunization. Our data show that purified rTsCRT induces polarized Th2 responses after oral immunization of mice, a common characteristic of protective immunity against helminths and, consequently, a desirable hallmark in the search for a vaccine.
Assuntos
Anticorpos Anti-Helmínticos/biossíntese , Calreticulina/imunologia , Taenia solium/imunologia , Administração Oral , Animais , Anticorpos Anti-Helmínticos/sangue , Western Blotting , Calreticulina/administração & dosagem , Calreticulina/isolamento & purificação , Citocinas/biossíntese , Ensaio de Imunoadsorção Enzimática , Fezes/química , Feminino , Imunidade nas Mucosas , Imunização/métodos , Imunoglobulina A/biossíntese , Imunoglobulina G/biossíntese , Injeções Subcutâneas , Intestino Delgado/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Mesentério , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Baço/citologia , Baço/imunologia , Teníase/prevenção & controleRESUMO
Transgenic plants are able to express molecules with antigenic properties. In recent years, this has led the pharmaceutical industry to use plants as alternative systems for the production of recombinant proteins. Plant-produced recombinant proteins can have important applications in therapeutics, such as in the treatment of rheumatoid arthritis (RA). In this study, the mycobacterial HSP65 protein expressed in tobacco plants was found to be effective as a treatment for adjuvant-induced arthritis (AIA). We cloned the hsp65 gene from Mycobacterium leprae into plasmid pCAMBIA 2301 under the control of the double 35S promoter from cauliflower mosaic virus. Agrobacterium tumefaciens bearing the pChsp65 plasmid was used to transform tobacco plants. Incorporation of the hsp65 gene was confirmed by PCR, reverse transcription-PCR, histochemistry, and western blot analyses in several transgenic lines of tobacco plants. Oral treatment of AIA rats with the HSP65 protein allowed them to recover body weight and joint inflammation was reduced. Our results suggest a synergistic effect between the HSP65 expressed protein and metabolites presents in tobacco plants.