Uso de fármacos anticorpos monoclonais, imunomoduladores e anti-inflamatórios no tratamento da infecção por COVID-19 / Use of monoclonal antibodies, immunomodulators, and anti-inflammatory drugs in the treatment of COVID-19

O objetivo deste estudo foi realizar o levantamento bibliográfico de artigos científicos e ensaios clínicos sobre a utilização de anticorpos monoclonais, imunomoduladores e anti-inflamatórios como possíveis alternativas terapêuticas para uso em pacientes com COVID-19, com ênfase nos mecanismos de ação e resultados de ensaios clínicos. Foram analisados artigos obtidos na base de dados MEDLINE® e ensaios clínicos disponíveis no site ClinicalTrials no período de 6 de abril a 6 de maio de 2020. Os ensaios realizados com os fármacos apresentados nesta revisão bibliográfica sugerem a viabilidade de uso de algumas dessas drogas como alternativas para tratamento da COVID-19. No entanto, observou-se que, em função do número reduzido de participantes dos estudos disponíveis, é indispensável a continuidade de pesquisas e dos ensaios clínicos com esses medicamentos, para estimar a eficácia dessas drogas no tratamento do SARS-CoV-2, contra o qual ainda não há terapia específica

The objective of this study was to carry out a bibliographic survey of scientific articles and current clinical trials on the use of monoclonal antibodies, immunomodulators, and anti-inflammatories as possible therapeutic alternatives for use in patients with COVID-19, highlighting their mechanisms of action and results of clinical trials. Articles from the MEDLINE® database and clinical trials available on the ClinicalTrials website were analyzedThe tests performed with the drugs presented in this bibliographic review suggest the feasibility of using some of these drugs as treatment alternatives for COVID-19. However, it was observed that the small samples evaluated in these tests make it imperative to proceed with research and clinical trials with these drugs to provide greater evidence of the effectiveness of these drugs in the treatment of the disease caused by SARS-CoV-2, for which there is no specific therapy so far.

Evaluación de la actividad inmunomoduladora de extractos metanólicos y de alcaloides de Berberis darwinii H. (Berberidaceae) / Evaluation of the immunomodulatory activity of methanolic extracts and alkaloids of Berberis darwinii H. (Berberidaceae)

Berberis darwinii Hook es una especie que habita el sur de Chile y la Patagonia, utilizada por la etnia mapuche para el tratamiento de procesos inflamatorios, estados febriles y dolor de estomacal. El propósito del siguiente estudio fue evaluar in vitro las propiedades del extracto total y de alcaloides de raíz de B. darwinii sobre viabilidad celular y la translocación del factor nuclear NF-kB en línea celular RAW 264.7. Se observó que los extractos no afectan negativamente la viabilidad en las células e inhibieron la translocación del factor nuclear NF-kB asociado a la modulación de la inflamación solo frente al extracto total. Estos resultados indicarían que B. darwinii podría inhibir algunos mecanismos específicos de la defensa celular al modular la translocación de NF- kB.

Berberis darwinii Hook is a species that inhabits southern Chile and Patagonia, used by the Mapuche ethnic group for the treatment of inflammatory processes, febrile states and stomach pain. The purpose of the following study was to evaluate in vitro the properties of the total extract and alkaloids of the root of B. darwinii on cell viability and the translocation of the nuclear factor NF-kB in cell line RAW 264.7. It was observed that the extracts did not negatively affect the viability in the cells and inhibited the translocation of the nuclear factor NF-kB associated with the modulation of inflammation only against the total extract. These results indicate that B. darwinii could inhibit some specific mechanisms of cell defense by modulating the translocation of NF-kB.

Immunostimulatory activity in mammalian cells of 3, 5-dihydroxy-7-methoxyflavanone ((-)-alpinone) isolated from Heliotropium huascoense resinous exudate / Actividad inmunoestimulante en células de mamífero de 3, 5-dihidroxi-7-metoxiflavanona ((-)-alpinona) aislada del exudado resinoso de Heliotropium huascoense

The flavonoid 3,5-dihydroxy-7-methoxyflavanone ((-)-alpinone) isolated from sticky resinous exudate of Heliotropium huascoense was evaluated as immunostimulatory in mammalian cells . Preliminary observations had showed that (-)-alpinone had increased the expression levels of pro-inflammatory cytokine transcripts in salmonid. Due to high morbidity and mortality that infectious diseases cause in humans, we evaluate the effect of (-)-alpinone as an immunostimulant in mammalian cells. Reactive oxygen species (ROS) are produced by macrophages activators for the destruction of pathogens; we evaluated (-)-alpinone effect in ROS generation and the proliferation of macrophages. The results showed that proliferation in Raw 264.7 cells treated with 10 and 25 µg/mL of (-)-alpinone had a significant increase in macrophage proliferation. In relation to ROS formation, cells treated with 1 and 5 µg/mL of (-)-alpinone, induce ROS formation in macrophages.

El flavonoide 3,5-dihidroxi-7-metoxiflavanona ((-)-alpinona) aislado del exudado resinoso de Heliotropium huascoense se evaluó como inmunoestimulador en células de mamíferos. Resultados preliminares habían demostrado que (-)-alpinona aumentaba los niveles de expresión de transcritos de citoquinas proinflamatorias en salmónidos. Debido a la alta morbilidad y mortalidad que causan las enfermedades infecciosas en los humanos, evaluamos el efecto de (-)-alpinona como inmunoestimulante en células de mamíferos. Dado que las especies de oxígeno reactivo (ROS) son producidas por macrófagos activados para la destrucción de patógenos, se evaluó el efecto de (- )-alpinona en la generación de ROS y la proliferación de macrófagos. Los resultados mostraron que la proliferación en células Raw264.7 tratadas con 10 y 25 µg / mL del flavonoíde tuvo un aumento significativo en la proliferación de macrófagos. En relación con la formación de ROS, las células tratadas con 1 y 5 µg/mL de (-)-alpinona, inducen la formación de ROS en los macrófagos.

Preclinical efficacy against toxic activities of medically relevant Bothrops sp. (Serpentes: Viperidae) snake venoms by a polyspecific antivenom produced in Mexico / Eficacia de un antiveneno poliespecífico producido en México para neutralizar, a nivel preclínico, las actividades tóxicas de venenos de Bothrops sp (Serpentes: Viperidae) de importancia médica

Abstract:The assessment of the preclinical neutralizing ability of antivenoms in Latin America is necessary to determine their scope of efficacy. This study was aimed at analyzing the neutralizing efficacy of a polyspecific bothropic-crotalic antivenom manufactured by BIRMEX in Mexico against lethal, hemorrhagic, defibrinogenating and in vitro coagulant activities of the venoms of Bothrops jararaca (Brazil), B. atrox (Perú and Colombia), B. diporus (Argentina), B. mattogrossensis (Bolivia), and B. asper (Costa Rica). Standard laboratory tests to determine these activities were used. In agreement with previous studies with bothropic antivenoms in Latin America, a pattern of cross-neutralization of heterologous venoms was observed. However, the antivenom had low neutralizing potency against defibrinogenating effect of the venoms of B. atrox (Colombia) and B. asper (Costa Rica), and failed to neutralize the in vitro coagulant activity of the venom of B. asper (Costa Rica) at the highest antivenom/venom ratio tested. It is concluded that, with the exception of coagulant and defibrinogenating activities of B. asper (Costa Rica) venom, this antivenom neutralizes toxic effects of various Bothrops sp venoms. Future studies are necessary to assess the efficacy of this antivenom against other viperid venoms. Rev. Biol. Trop. 65 (1): 345-350. Epub 2017 March 01.

ResumenEs necesario estudiar a nivel preclínico la capacidad neutralizante de los antivenenos producidos en América Latina, para conocer su espectro de cobertura. En este estudio se analizó la eficacia preclínica de un antiveneno poliespecífico botrópico-crotálico producido por BIRMEX, en México, para neutralizar los efectos letal, hemorrágico, desfibrinogenante y coagulante in vitro de los venenos de Bothrops jararaca (Brasil), B. atrox (Perú y Colombia), B. diporus (Argentina), B. mattogrossensis (Bolivia) y B. asper (Costa Rica). Se emplearon metodologías de laboratorio estándar en los análisis. En consonancia con estudios anteriores con diversos antivenenos botrópicos en América Latina, se observó un amplio patrón de neutralización de estos venenos heterólogos en la mayoría de los efectos estudiados. Sin embargo, el antiveneno mostró una baja capacidad neutralizante contra el efecto desfibrinogenante de los venenos de B. atrox (Colombia) y B. asper (Costa Rica) y no neutralizó la actividad coagulante in vitro del veneno de B. asper (Costa Rica) a la máxima razón antiveneno/ veneno empleada.

The potential molecular effects of bursal septpeptide II on immune induction and antitumor activity

The bursa of Fabricius (BF) is the acknowledged central humoral immune organ in birds. Bursal septpeptide II (BSP-II) is an immunomodulatory bioactive peptide isolated from BF. To understand the effects of BSP-II on immune induction, gene expression profiles of hybridoma cells treated with BSP-II were evaluated. Pathway analysis showed that regulated genes were involved in cytokine-cytokine receptor interactions, T cell receptor signaling pathway, and pathway in cancer. It was observed that BSP-II reduced tumor cells proliferation and stimulated p53 expression. These results indicate potential mechanisms underlying the effects of the humoral immune system on immune induction, including antitumor activities. Our study has provided a novel insight into immunotherapeutic strategies for treating human tumors.

Effect of mouse antisera targeting the Phlebotomus papatasi midgut chitinase PpChit1 on sandfly physiology and fitness

In sandflies, the absence of the peritrophic matrix (PM) affects the rate of blood digestion. Also, the kinetics of PM secretion varies according to species. We previously characterised PpChit1, a midgut-specific chitinase secreted in Phlebotomus papatasi (PPIS) that is involved in the maturation of the PM and showed that antibodies against PpChit1 reduce the chitinolytic activity in the midgut of several sandfly species. Here, sandflies were fed on red blood cells reconstituted with naïve or anti-PpChit1 sera and assessed for fitness parameters that included blood digestion, oviposition onset, number of eggs laid, egg bouts, average number of eggs per bout and survival. In PPIS, anti-PpChit1 led to a one-day delay in the onset of egg laying, with flies surviving three days longer compared to the control group. Anti-PpChit1 also had a negative effect on overall ability of flies to lay eggs, as several gravid females from all three species were unable to lay any eggs despite having lived longer than control flies. Whereas the longer survival might be associated with improved haeme scavenging ability by the PM, the inability of females to lay eggs is possibly linked to changes in PM permeability affecting nutrient absorption.

Ocorrência e distribuição de BanLec em cultivares de banana e avaliação da sua atividade imunomoduladora in vivo / Occurrence and distribution of BanLec in banana cultivars and evaluation of its immunomodulatory activity in vivo

Lectinas são proteínas cuja principal característica é a de se ligar específica e reversivelmente a carboidratos. BanLec é a lectina presente na polpa de bananas, que se liga especificamente a manose e glicose, e é capaz de induzir a proliferação de células T, podendo estimular a resposta imune. Existem indícios de que o teor de BanLec pode variar dependendo do estádio de amadurecimento e do tipo de cultivar, o que pode afetar a quantidade de BanLec existente na fruta quando consumida in natura e a possível resposta imune frente ao consumo de banana. Por este motivo, um dos objetivos desse trabalho foi determinar os teores e a atividade hemaglutinante de BanLec em extratos de farinha de banana verde, além de bananas das cultivares Pacovan, Figo, Terra, Mysore e Nanicão, nos estádios de maturação verde e maduro, e submetidas a tratamento com 1-MCP e baixa temperatura (para cv. Nanicão). Com vista a atender ao objetivo de avaliar seus efeitos imunomoduladores in vivo, a BanLec foi purificada da cultivar Nanicão e administrada por via oral a camundongos BALB/c. Os ensaios de atividade hemaglutinante dos extratos de banana apontaram para maior quantidade de BanLec no fruto maduro, quando comparado ao verde, e ausência dessa proteína na cultivar Figo. Os parâmetros imunológicos analisados após administração de BanLec aos camundongos demonstram que a resposta imune gerada após ingestão de BanLec é dose dependente, além disso, a administração de 50 µg de BanLec aos animais foi capaz de modular citocinas importantes na resposta imunológica, provavelmente causando um efeito que pode ser interpretado como mais protetor do que patogênico. Com base nos resultados obtidos, podemos concluir que existem diferenças nos teores de BanLec dependendo da cultivar e estádio de maturação analisado, sendo que essa proteína não está presente na polpa de todas as variedades de banana e finalmente, que ela tem grande potencial imunomodulador in vivo, uma vez que ativou citocinas de resposta anti-inflamatória

Lectins are proteins which bind specifically and reversibly to carbohydrates. BanLec is the lectin present in banana pulp, and it binds to mannose and glucose, being capable of inducing T-cell proliferation, and to stimulate the immune response. There are some evidence that the amount of BanLec may vary depending on the maturation stage of the fruit and the cultivar (cv.), which may affect the amount of BanLec and the possible immune response after consumption of banana. Thus, this study aimed to evaluate the amount of BanLec and its hemagglutinating activity in crude extracts of bananas from cultivars Pacovan, Figo, Terra, Mysore and Nanicão, in both unripe and ripe maturation stage, and also fruits which were treated with 1-MCP and low temperature. In addition, in order to access their immunomodulatory effects in vivo, BanLec was purified by affinity chromatography and administered orally to BALB/c mice. The hemagglutinating activity assays indicate higher amount of BanLec in ripe fruit. Moreover, the possible was undetectable in the pulp of banana Figo. The immunological parameters of mice orally fed with BanLec showed that the immunological response is dependent on the amount of protein administrated, in agreement to previous in vitro studies. Besides, 50 µg of BanLec, were able to modulate some cytokines in immune response, causing an effect that seems to be more protective than pathogenic. We conclude that there are important differences in amount of BanLec depending on the cultivar and the maturation stage, and BanLec has a dose-dependent immunomodulatory effect in vivo

Immunomodulatory effects of Pimpinella anisum L. (Aniseed) in Broiler Chicks against Newcastle disease and infectious bursal disease viruses / Efecto inmunomodulador de Pimpinella anisum L. (anís) en pollos de engorde contra la enfermedad de Newcastley la enfermedad viral de la bursitis infecciosa

Pimpinella anisum L. (Aniseed) is mostly used as an immune stimulant, growth promoter, antifungal, antibacterial in many countries for centuries. The aim of this study was to determine the immunomodulatory effect of aniseed against Newcastle Disease (ND) and infectious bursal disease (IBD) viruses. The immunomodulatory effect of aniseed against ND and IBD viruses were determined by modifying splenic cell migration inhibition assay and differential leukocyte count for cellular immunity. Haemagglutination inhibition and indirect haemagglutination were used for measurement of humoral immune response against ND and IBD viruses, respectively. The present study suggests that the aniseed addition to basal diet at the rate of 0.5 g/kg and 1 g/kg of feed had best immunomodulatory activity both for humoral and cellular immune responses. However, at higher doses aniseed had adverse effects. Aniseed possesses significant immunomodulatory activity when it is added at lower doses i.e., 0.5 g/kg and 1 g/kg.

Pimpinella anisum L. (Anís) se utiliza principalmente como un estimulante inmunológico, promotor del crecimiento, antifúngico, y antibacteriano, en muchos países durante siglos. El objetivo de este estudio fue determinar el efecto inmunomodulador de anís contra la enfermedad de Newcastle (ND) y la enfermedad de la bursitis infecciosa (IBD). El efecto inmunomodulador de anís contra los virus ND y e IBD se determinaron mediante la modificación del ensayo de inhibición de la migración de células del bazo y recuento diferencial de leucocitos de la inmunidad celular. La inhibición de la hemaglutinación y hemaglutinación indirecta se utilizaron para la medición de la respuesta inmune humoral contra el virus de ND e IBD, respectivamente. El presente estudio sugiere que la adición de anís a la dieta basal a la tasa de 0,5 g/kg y 1 g/kg de alimentación tuvo una mejor actividad inmunomoduladora tanto para las respuestas inmunes humorales como celulares. Sin embargo, a dosis más altas de anís tuvo efectos adversos. El anís posee una importante actividad inmunomoduladora cuando se añade en dosis más bajas, es decir, 0,5 g/kg y 1 g/kg.

Flavonoids Modulate the Proliferation of Neospora caninum in Glial Cell Primary Cultures

Neospora caninum (Apicomplexa; Sarcocystidae) is a protozoan that causes abortion in cattle, horses, sheep, and dogs as well as neurological and dermatological diseases in dogs. In the central nervous system of dogs infected with N. caninum, cysts were detected that exhibited gliosis and meningitis. Flavonoids are polyphenolic compounds that exhibit antibacterial, antiparasitic, antifungal, and antiviral properties. In this study, we investigated the effects of flavonoids in a well-established in vitro model of N. caninum infection in glial cell cultures. Glial cells were treated individually with 10 different flavonoids, and a subset of cultures was also infected with the NC-1 strain of N. caninum. All of the flavonoids tested induced an increase in the metabolism of glial cells and many of them increased nitrite levels in cultures infected with NC-1 compared to controls and uninfected cultures. Among the flavonoids tested, 3',4'-dihydroxyflavone, 3',4',5,7-tetrahydroxyflavone (luteolin), and 3,3',4',5,6-pentahydroxyflavone (quercetin), also inhibited parasitophorous vacuole formation. Taken together, our findings show that flavonoids modulate glial cell responses, increase NO secretion, and interfere with N. caninum infection and proliferation.

Efecto de Lepidium meyenii (maca) sobre la producción de tres citoquinas hematopoyéticas en esplenocitos de ratones inmunosuprimidos / Effect of Lepidium meyenii (maca) on the production of three hematopoietic cytokines in splenocytes from immunosuppressed mice

Lepidium meyenii Walp, Brassicaceae (Maca) is a plant native to Peru to conferring immunostimulatory activity. The objective was to evaluate the immunomodulatory effect of the aqueous extract (EAc) of yellow ecotype on gene expression of three hematopoietic cytokines (IL-3, GM-CSF and IL-7) in splenocytes from Balb/c mice immunosuppressed with cyclophosphamide. Levels of mRNA were measured by RT-PCR. Two days after immunosuppression (IS), in splenocytes from mice treated with EAc increased expression of mRNA was demonstrated for IL-3, GM-CSF e IL-7 (p < 0.05) compared to the untreated group. Five days after IS, in mice treated with EAc found higher cell counts in bone marrow, peripheral blood and endogenous colonies formed units in spleen compared to the untreated group. It is concluded that administration of EAc in immunocompromised mice can reverse the suppressive effects of cyclophosphamide.

Lepidium meyenii Walp., Brassicaceae (Maca) es una planta oriunda del Perú a la que se atribuye actividad inmunoestimuladora. El objetivo fue evaluar el efecto inmunomodulador del extracto acuoso (EAc) del ecotipo amarillo sobre la expresión génica de tres citoquinas hematopoyéticas (IL-3, GM-CSF e IL-7) en esplenocitos de ratones Balb/c inmunosuprimidos con ciclofosfamida. Los niveles de mRNA se midieron por RT-PCR. Dos días después de la inmunosupresión (IS), en los esplenocitos de los ratones tratados con EAc se evidenció mayor expresión de mRNA para IL-3, GM-CSF e IL-7 (p<0.05) respecto al grupo no tratado. Cinco días después de la IS, en los ratones tratados con EAc se encontró mayor recuento de células en la médula ósea, sangre periférica y unidades formadoras de colonias endógenas en el bazo respecto al grupo no tratado. Se concluye que la administración de EAc a ratones inmunocomprometidos puede revertir los efectos supresores de la ciclofosfamida.

Efeito anti-inflamatório dos macrolídeos em doenças pulmonares da infância / Anti-inflammatory effects of macrolides in childhood lung diseases

Os macrolídeos são fármacos com efeitos antimicrobianos especialmente contra patógenos intracelulares. Vários estudos têm demonstrado possíveis efeitos anti-inflamatórios dos macrolídeos. Esses medicamentos inibem a produção de algumas interleucinas e podem reduzir a inflamação neutrofílica pulmonar. Ensaios clínicos têm demonstrado efeitos benéficos dos macrolídeos em diversas doenças pulmonares crônicas. O objetivo deste estudo foi revisar os dados recentes da literatura médica sobre os efeitos anti-inflamatórios dos macrolídeos nas doenças respiratórias da infância, através da pesquisa da base de dados Medline (PubMed) dos seguintes termos em inglês: "macrolide and cystic fibrosis"; "macrolide and asthma"; "macrolide and bronchiolitis obliterans"; e "macrolide and acute bronchiolitis" Foram selecionados artigos publicados em revistas científicas internacionais entre 2001 e 2012. Estudos clínicos e evidências in vitro comprovam o efeito anti-inflamatório dos macrolídeos em doenças respiratórias. Alguns ensaios clínicos demonstram benefícios na administração de macrolídeos em pacientes com fibrose cística; porém, o risco de resistência bacteriana deve ser considerado na análise desses benefícios. Tais benefícios são controversos em outras doenças respiratórias, e seu uso rotineiro não está indicado. Mais estudos clínicos controlados são necessários para avaliar a eficácia desses medicamentos como anti-inflamatórios. Dessa forma, poderemos definir melhor os benefícios dos macrolídeos no tratamento de cada uma das situações clínicas especificadas.

Macrolides are drugs that have antimicrobial effects, especially against intracellular pathogens. Various studies have shown that macrolides might also have anti-inflammatory effects. Macrolides inhibit the production of interleukins and can reduce pulmonary neutrophilic inflammation. Clinical trials have demonstrated beneficial effects of macrolides in various chronic lung diseases. The objective of this study was to review recent data in the medical literature on the anti-inflammatory effects of macrolides in childhood lung diseases by searching the Medline (PubMed) database. We used the following search terms: "macrolide and cystic fibrosis"; "macrolide and asthma"; "macrolide and bronchiolitis obliterans"; and "macrolide and acute bronchiolitis". We selected articles published in international scientific journals between 2001 and 2012. Clinical studies and in vitro evidence have confirmed the anti-inflammatory effect of macrolides in respiratory diseases. Some clinical trials have shown the benefits of the administration of macrolides in patients with cystic fibrosis, although the risk of bacterial resistance should be considered in the analysis of those benefits. Such benefits are controversial in other respiratory diseases, and the routine use of macrolides is not recommended. Further controlled clinical trials are required in order to assess the efficacy of macrolides as anti-inflammatory drugs, so that the benefits in the treatment of each specific clinical condition can be better established.

Efeito imunomodulador de hipoglicemiantes orais em cultura de linfócitos de pacientes com diabetes tipo 2 / Immunomodulatory effects of oral antidiabetic drugs in lymphocyte cultures from patients with type 2 diabetes

INTRODUCTION AND OBJECTIVE: It has been suggested that type 2 diabetes is an inflammatory response manifestation. The main drugs used to treat type 2 diabetes are sulphonylureas and biguanides. The aim of this study was to demonstrate the modulatory effects of oral hypoglycemic drugs (chlorpropamide and metformin) on lymphocyte proliferation in vitro and ex vivo. METHODS: Peripheral blood mononuclear cells were isolated from human blood by gradient centrifugation. T-lymphocytes were stimulated by phytohemagglutinin (PHA) and oral hypoglycemic drugs. RESULTS: In both in vitro and ex vivo experiments, there was a reduction in cell proliferation after treatment with oral hypoglycemic drugs. When both drugs were used in combination, a high level of cytotoxicity was observed, which made analysis of immunomodulatory effects unfeasible. DISCUSSION AND CONCLUSION: We demonstrated that diabetes itself may reduce cell proliferation significantly when stimulated by PHA, which may indicate that diabetic patients have difficulties in promoting an efficient inflammatory response. Moreover, the use of oral hypoglycemic drugs may aggravate this situation.

INTRODUÇÃO E OBJETIVOS: Tem sido sugerido que o diabetes mellitus tipo 2 (DM2) é uma manifestação da resposta inflamatória. As principais drogas utilizadas no tratamento do DM2 são as sulfonilureias e as biguanidas. O objetivo deste trabalho é demonstrar os efeitos moduladores na proliferação de linfócitos causada pelos hipoglicemiantes orais (clorpropamida e metformina), in vitro e ex vivo. MÉTODOS: Células mononucleares de sangue periférico foram isoladas de seres humanos por gradiente de centrifugação. Os linfócitos T foram estimulados com fito-hemaglutinina (PHA) e hipoglicemiantes. RESULTADOS: Nos experimentos in vitro e ex vivo, mostramos a redução da proliferação celular quando do tratamento com drogas hipoglicemiantes orais. Quando as drogas foram utilizadas em combinação, foi observado alto grau de citotoxicidade, tornando inviável a análise do efeito imunomodulador. DISCUSSÃO E CONCLUSÃO: Mostramos que o diabetes, por si, pode reduzir significativamente a proliferação celular quando estimulada por PHA, o que pode indicar que o paciente diabético tem dificuldade em promover a eficiente resposta inflamatória e que o uso de hipoglicemiantes pode piorar esta situação.

Immunomodulatory effects of astragalus gypsicolus hydroalcoholic extract in ovalbumin-induced allergic mice model

Several studies have demonstrated that herbal extracts possess various biological effects including anti-inflammatory and anti-cancer activities. The present study was aimed to investigate the protective effects of the Astragalus gypsicolus [AG] hydroalcoholic extract in early allergic sensitized mice induced by ovalbumin. Phytochemical assay was used to recognize the main active constituents in the AG hydroalcoholic extract. Mice were immunized with subcutaneous injection of ovalbumin and aluminum hydroxide. Efficiency of sensitization was assessed by serum IgE levels and eosinophil count. After sensitization, two doses of extract [250 mg/kg and 500 mg/kg] were injected intrapritoneally. On day 14, mice were challenged with intrapritoneal injection of ovalbumin. IL-4 and IFN gamma levels in broncoalveolar lavage fluid, which had been collected on day 15, were assessed by Enzyme-Linked Immunosorbent Assay [ELISA] kit. Our results indicate two main active constituents including flavonoids and terpenoids are present in the AG.hydroalcoholic extract. Intrapritoneal injection of the AG hydroalcoholic extract was able to decrease IL-4 and increase IFN gamma. It seems the AG hydroalcoholic extract has the potential to modulate the balance of Thl/Th2 cytokines in allergy

Immunomodulatory effects of betulinic acid from the bark of white birch on mice

The objective of this study was to explore the immunomodulatory effects of betulinic acid (BA) extracted from the bark of white birch on mice. Female mice were orally administered BA for 14 days in doses of 0, 0.25, 0.5, and 1 mg/kg body weight. We found that BA significantly enhanced the thymus and spleen indices, and stimulated lymphocyte proliferation induced by Concanavalin A and lipopolysaccharide as shown by MTT assay. Flow cytometry revealed that BA increased the percentage of CD4+ cells in thymus as well as the percentage of CD19+ and the ratios of CD4+/CD8+ in spleen. BA increased the number of plaque-forming cell and macrophage phagocytic activity as indicated by a neutral red dye uptake assay, and the peritoneal macrophages levels of TNF-alpha were also increased. In contrast, serum levels of IgG and IgM and serum concentrations of IL-2 and IL-6 were significantly decreased in BA-treated mice compared to the control as assayed by haemagglutination tests and ELISA, respectively. Taken together, these results suggest that BA enhances mouse cellular immunity, humoral immunity, and activity of macrophages. Thus, BA is a potential immune stimulator and may strengthen the immune response of its host.

Efficacy of Dendritic Cells Matured Early with OK-432 (Picibanil(R)), Prostaglandin E2, and Interferon-alpha as a Vaccine for a Hormone Refractory Prostate Cancer Cell Line

Dendritic cells (DCs) are potent antigen-presenting cells. OK432 (Picibanil(R)) was introduced as a potent stimulator of DC maturation in combination with prostaglandin-E2 and interferon-alpha. We compared the efficacy of a DC-prostate cancer vaccine using early-mature DCs stimulated with OK432, PGE2 and INF-alpha (OPA) with that of vaccines using other methods. On days 3 or 7 of DC culture, TNF-alpha (T), TNF-alpha and LPS (TL) or OPA were employed as maturation stimulators. DU145 cells subjected to heat stress were hybridized with mature DCs using polyethyleneglycol. T cells were sensitized by the hybrids, and their proliferative and cytokine secretion activities and cytotoxicity were measured. The yields of early-mature DCs were higher, compared to yields at the conventional maturation time (P<0.05). In the early maturation setting, the mean fusion ratios, calculated from the fraction of dual-positive cells, were 13.3%, 18.6%, and 39.9%, respectively (P=0.051) in the T only, TL, and OPA-treated groups. The function of cytotoxic T cells, which were sensitized with the hybrids containing DCs matured early with OPA, was superior to that using other methods. The antitumor effects of DC-DU145 hybrids generated with DCs subjected to early maturation with the OPA may be superior to that of the hybrids using conventional maturation methods.

Investigating the effect of the homeopathic immunomodulator, MODUL8® on Blood count, bronchial lavage and fibrin ultrastructure on experimental asthmatic BALB/c mice / Investigación del efecto del inmunomodulador homeopatico Modul8® sobre sangre, lavado bronquial y ultraestructura de la fibrina en ratones experimentales asmáticos BALB/c

Modul8® is a composite mixture of natural products that are known to be an immunomodulator. In the current study the effect of this immunomodulator is tested on an experimental asthmatic BALB/c mouse model to investigate its properties on the white blood cell count in the blood and bronchial lavage of the animals since white blood cells play a fundamental role in the inflammatory process involved in asthma. As it is known that platelets also play an important role in the immune system, the ultrastructure of platelets and fibrin networks were also investigated by scanning electron microscopy. The animals were sensitised, nebulized and treated over a period of 43 days until termination. Results from the blood smears as well as the bronchial lavage smears revealed significantly higher eosinophil counts in the asthmatic group compared to the control and treated groups. Changes in the ultrastructure of the platelets and fibrin networks could also be observed, with the Modul8® -treated group appearing similar to that of the control group where thick major and thin minor fibres could clearly be distinguished and a tight mass of platelet aggregate could be observed. Whereas the fibrin networks from the asthmatic animals appeared flimsy with a tight mass of thin fibres covering the thick major fibres. The asthmatic platelet aggregates appeared granular without the tight round appearance of the control platelet aggregates. It is therefore concluded that Modul8® positively influences the white blood cell counts by altering the asthmatic profile to look similar to that of the control. Also, it seems as if Modul8® has a stabilizing effect on the platelets and fibrin networks. From these results it can be suggested that Modul8® might successfully be used in the treatment of inflammatory conditions such as asthma.

Modul8® es una mezcla compuesta de productos naturales que es conocida por ser un inmunomodulador. En el presente estudio, el efecto de este inmunomodulador se prueba de forma experimental en el modelo de ratón asmáticos BALB/c, para investigar sus propiedades sobre el conteo de glóbulos blancos en la sangre y lavado bronquial de los animales, ya que los glóbulos blancos desempeñan un papel fundamental en el proceso de respuesta inflamatoria implicado en el asma. Como es sabido, también las plaquetas desempeñan un papel importante en el sistema inmunológico, así, la ultraestructura de las plaquetas y las redes de fibrina también fueron investigadas por microscopía electrónica de barrido. Los animales fueron sensibilizados, nebulizados y tratados durante un período de 43 días hasta el término. Los resultados de los frotis de sangre, así como los de lavado bronquial revelaron un número significativamente mayor de eosinófilos en el grupo de asmáticos en comparación con el control y grupos tratados. Cambios en la ultraestructura de las plaquetas y redes de fibrina también pueden ser observados, donde el grupo tratado con la Modul8® aparece similar a el grupo control, donde los fibras de mayor grosor y menor grosor pueden ser claramente distinguidas y además, puede ser observada una apretada masa de plaquetas aglutinadas. Considerando las redes de la fibrina en animales asmáticos parecen endebles con una apretada masa de fibras de menor grosor que cubren las fibras de mayor grosor. Los agregados de plaquetas en asmáticos aparecen granulares sin el aspecto apretado del agregado plaquetario que rodea al grupo control. Por tanto, se concluye que Modul8® positivamente influye en el conteo de glóbulos blancos mediante la alteración del perfil de asmáticos a un aspecto similar al del control. Además, parece como si Modul8® tuviera un efecto estabilizador en las plaquetas y las redes de fibrina. De estos resultados se puede sugerir que Modul8® puede ser utilizado...

Terapia con inmunoglobulina endovenosa: mecanismos de acción, usos e indicaciones / Intravenous immunoglobulin treatment: mechanisms of action, uses and indications

Los anticuerpos o inmunoglobulinas forman parte de la inmunidad humoral y son producidos por los linfocitos B. Sus funciones incluyen neutralización, opsonización y fagocitosis de microorganismos y toxinas, activación del complemento y citotoxicidad dependiente de anticuerpos (ADCC). Hace más de 50 años las preparaciones de inmunoglobulina humana endovenosa (IGIV) han sido utilizadas tanto como terapias de reemplazo en inmunodeficiencias como en tratamientos inmunomoduladores/antiinflamatorios.Los mecanismos de acción se pueden clasificar en antiinfectivos y en inmunomoduladores-antiinflamatorios. Los primeros se basan en la restauración de los niveles de anticuerpos tanto patógeno-específicos como naturales, lo que lleva al desarrollo de una respuesta inmune humoral normal. El segundo mecanismo es más complejo y comprende la neutralización de autoanticuerpos, modulación de citoquinas e inhibición del complemento, entre otros.Sus indicaciones en la actualidad incluyen algunas inmunodeficiencias primarias y secundarias, además de ciertas enfermedades autoinmunes y desórdenes inflamatorios sistémicos.

Antibodies or immunoglobulins make up part of humoral immunity and are produced by B lymphocytes. Functions include neutralization, opsonization and phagocytosis of microorganisms and toxins, complement activation and antibody-dependent cellular cytotoxicity (ADCC). Preparations of intravenous human immunoglobulin (IGIV) have been used for more than fifty years in both replacement therapies in immunodeficiency and in immunomodulatory / anti-inflammatory treatments. Mechanisms of action can be classified in anti-infective and in immunomodulatory / anti-inflammatory. The first are based on the restoration of both pathogen-specific and natural antibodies, which leads to a normal humoral immune response. The second is more complex and includes antibody neutralization, cytokine modulation and complement inhibition, among others.Present-day indications include primary and secondary immunodeficiencies, as well as certain autoimmune diseases and systemic inflammatory disorders.

Avances en esclerosis múltiple: tratamiento / Advances in multiple sclerosis: treatment

En los últimos 10 años el estudio de la Esclerosis Múltiple (EM) ha presentado numerosos avances clínicos y terapéuticos, que han permitido un manejo más racional de la enfermedad, con significativo beneficio para los pacientes. De ser una enfermedad crónica sin tratamientos específicos, actualmente existen al menos seis fármacos con demostrada actividad sobre la enfermedad, y herramientas útiles para establecer pronósticos y controlar la evolución. En el presente trabajo (dividido en dos partes) se analizaran algunos aspectos de los avances observados en EM, especialmente aquellos que han incidido directa o indirectamente en un beneficio para los pacientes, y que apuntan a un tratamiento precoz de la enfermedad.

New data gathered for the past 5-10 years suggest that it is possible to define the rísk of clinically definite MS, as well as long term disability. This is specially significant in patients presenting with a Clinically Isolated Syndrome (OS), based on clinical presentation and MRI imaging. Longitudinal studies of patients with OS have permitted the realization of clinical trials of early treatment with Interferon Beta (1 a, 1 b) and Glatiramer acetate on these patients. These trials have shown significant benefit with all these treatments, and it is expected a better prognosis for patients with Multiple Sclerosis at early stages.

Evaluation of immunomodulatory and anti-inflammatory effects and phytochemical screening of Alternanthera tenella Colla (Amaranthaceae) aqueous extracts

Alternanthera tenella Colla extracts are used in Brazilian traditional folk medicine to treat a variety of infectious diseases as well as inflammation and fever. In this work, the immunomodulatory, anti-inflammatory and potential toxic effects of cold (CAE) and hot (HAE) aqueous extracts of A. tenella were investigated in vivo. In addition, we analyzed the phytochemical properties of both extracts. BALB/c mice were immunized in vivo with sheep red blood cells and concomitantly inoculated intraperitoneally (i.p.) with each extract (50, 100 or 200 mg/kg). Specific antibody-producing cells were enumerated using plaque-forming cell assays (PFC) and anti-SRBC IgG and IgM serum levels were measured via enzyme-linked immunosorbent assay. Body and lymphoid organ weights were determined after treatments in order to evaluate toxic effects. Carrageenan-induced paw edema was employed to investigate anti-inflammatory activity in mice inoculated i.p. with CAE or HAE (200 or 400 mg/kg). Phytochemical screening was performed using spectrometric and chromatographic approaches and revealed that CAE possessed higher tannin and flavonoid levels than HAE. PFC numbers were increased after treatment with CAE (100 mg/kg) four days after immunization, as were the serum antibody titers after four and seven days, suggesting immunostimulatory activity through modulation of B lymphocyte functions. Body and organ weights did not show major changes, suggesting that extracts administered to mice did not induce significant toxicity. Both extracts had significant anti-inflammatory activity in the paw edema assay. These results suggested that aqueous extracts from A. tenella contained several chemical compounds that possess positive and/or negative modulator effects on the immune system, which appeared to correlate with tannin and flavonoid levels in those extracts. In summary, these studies provide important insight into the biological activities of A. tenella.