RESUMO
INTRODUCCIÓN: La seroprevalencia del SARS-CoV-2 en las enfermedades inflamatorias inmunomediadas (IMID) sigue siendo fuente de controversia. OBJETIVO: Comparar la seroprevalencia de anticuerpos (Ac) anti SARS-CoV-2 en pacientes con IMID en tratamientos con fármacos antirreumáticos modificadores de la enfermedad biológicos (FAMEb) o sintéticos dirigidos (FAMEsd) frente a un grupo de personas sin IMID. MÉTODOS: Estudio de pacientes con IMID y tratamientos con FAMEb y FAMEsd y de individuos sin IMID. Mediante la técnica de inmunoensayo por quimioluminiscencia indirecta, se determinaron las serologías IgG frente al SARS-CoV-2 entre octubre/2020 y mayo/2021. RESULTADOS: Se estudiaron 1.100 sujetos, 550 pacientes con IMID y 550 personas sin IMID. Se observó una seroprevalencia de 16% (88/550) en los pacientes frente a 19,3% (106/550) en el grupo de personas sin IMID, sin significación estadística (OR 0,790 [IC 95% 0,558-1,118]). Comparando los tratamientos con FAMEb o FAMEsd, se observó una tendencia a una menor seroprevalencia con rituximab, en relación con los individuos sin IMID (OR 0,296 [IC 95% 0,0871,007]). Asimismo, se encontró menor seroprevalencia en los pacientes que además de su FAMEb recibían tratamiento con metotrexato, en comparación con el grupo de personas sin IMID (OR 0,432 [IC 95% 0,223-0,835]). CONCLUSIONES: Las IMID en tratamiento con FAMEb o FAMEsd no influyen en la seroprevalencia frente al SARS-CoV-2 de los pacientes. El tratamiento concomitante con metotrexato disminuye de forma significativa la seroprevalencia en estos pacientes.
BACKGROUND: The seroprevalence of SARS-CoV-2 in immunemediated inflammatory diseases (IMID) remains controversial. AIM: To compare the seroprevalence of antibodies (Ab) to SARS-CoV-2 in patients with IMID receiving treatment with biological diseasemodifying antirheumatic drugs (bDMARD) or targeted synthetic (tsDMARD) versus a group of people without IMID. METHODS: Study of patients with IMID and treatments with bDMARD and tsDMARD and individuals without IMID. IgG serology against SARS-CoV-2 was measured using the two-step sandwich immunoassay technique by indirect chemiluminescence between October 2020 and May 2021. RESULTS: A total of 1100 subjects were studied, 550 patients with IMID and 550 persons without IMID. A seroprevalence of 16% (88/550) was observed in patients versus 19.3% (106/550) in the group of people without IMID, without statistical significance (OR 0.790 [95% CI 0.558-1.118]). Comparing the treatments with bD- MARD or tsDMARD, there was a tendency to lower seroprevalence with rituximab, in relation to individuals without IMID (OR 0.296 [95% CI 0.087-1.007]). In addition, lower seroprevalence was found in patients who received methotrexate treatment in addition to their bDMARD, compared to the group of individuals without IMID (OR 0.432 [95% CI 0.223-0.835]). CONCLUSIONS: IMIDs in treatment with bDMARDs or tsDMARDs do not influence the seroprevalence against SARS-CoV-2 in patients. Concomitant treatment with methotrexate significantly decreased seroprevalence in these patients.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , COVID-19/epidemiologia , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/epidemiologia , Terapia Biológica , Imunoglobulina G/imunologia , Estudos Soroepidemiológicos , Prevalência , Estudos Transversais , Antirreumáticos/uso terapêutico , Medicamentos Biossimilares , COVID-19/imunologiaRESUMO
ANTECEDENTES: El presente dictamen expone la evaluación de la eficacia y seguridad de romiplostim en pacientes pediátricos con trombocitopenia inmune primaria crónica, respuesta inadecuada o intolerancia a inmunoglobulina, corticoesteroides y eltrombopag, no candidatos a esplenectomia. ASPECTOS GENERALES: La trombocitopenia inmunitaria (TPI), anteriormente conocida como púrpura trombocitopénica idiopática o púrpura trombocitopénica inmunitaria, es una enfermedad autoinmune caracterizada por la disminución de plaquetas (conteo de plaquetas menor de 100 x 109/L con conteo normal de células blancas y hemoglobina) (Bussel 2020). La TPI es considerada primaria cuando no existen causas o desórdenes que puedan estar asociados a la trombocitopenia, y crónica cuando tiene una duración mayor a 12 meses (Bussel 2020). En Estados Unidos, entre el 2011 y el 2016, la TPI crónica en niños menores de 18 años representó el 15.9 % de los casos de TPI (Shaw et al. 2019). En Perú no se han reportado datos epidemiológicos de la TPI en niños. La TPI es una enfermedad infrecuente cuyas estimaciones más robustas de su incidencia anual están en el rango de 1.9 a 6.4 casos por cada 100,000 niños (Terrell et al. 2010). Dada la poca frecuencia de la enfermedad, los estimados de mortalidad son escasos; pero se señala que la mortalidad en pacientes pediátricos con TPI es muy rara. La mortalidad en los pacientes recién diagnosticados se debe principalmente a las complicaciones del sangrado (e.g. hemorragia intracraneal); pero en los pacientes con TPI crónica puede ocurrir por complicaciones del tratamiento inmunosupresor de largo plazo (Bussel 2022). La incidencia de hemorragia intracraneal también es infrecuente (menor al 1 %); sin embargo, sería ligeramente mayor en los pacientes con TPI crónica (Psaila et al. 2009). TECNOLOGÍA SANITARIA DE INTERÉS: Romiplostim (NPLATE ®, AMGEN) es un TPO-RA que pertenece a la clase de agonistas miméticos (FDA 2020). Romiplostim es una proteína de fusión que media y activa las vías de transcripción intracelular a través del receptor de TPO para aumentar la producción de plaquetas (Tecnofarma 2020). Este medicamento se obtiene por tecnología de ácido desoxirribonucleico recombinante en E. coli (Tecnofarma 2020). METODOLOGÍA: La búsqueda de la literatura se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de romiplostim, comparado con la mejor terapia de soporte (corticoesteroides e inmunoglobulina), en pacientes pediátricos con trombocitopenia inmune primaria crónica, respuesta inadecuada o intolerancia a inmunoglobulina, corticoesteroides e intolerancia a eltrombopag, no candidatos a esplenectomía. La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, LILACS y The Cochrane Library. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), Scottish Medicines Consortium (SMC), Agency for Healthcare Research and Quality's (AHRQ), National Health and Medical Research Council (NHMRC), New Zealand Guidelines Group (NZGG), Haute Autorité de Santé (HAS), Institute for Clinical and Economic Review (ICER), y Comissáo nacional de incorpornáo de tecnologías no sus (CONITEC), Canadian Medical Association (CMA), American College of Physicians Clinical Practice Guidelines, American Society of Hematology (ASH), y Registered Nurses Association of Ontario (RNAO). Adicionalmente, se realizó una búsqueda manual en las bases The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y el repositorio institucional de la Dirección General de Medicamentos, Insumos y Drogas (DIGEMID). Asimismo, se colectó información sobre el medicamento de interés del presente dictamen en las páginas web de la European Medicines Agency (EMA), y Food and Drug Administration (FDA). Finalmente, se realizó una búsqueda manual en el portal ClinicalTrials.govdel National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. RESULTADOS: Guías de práctica clínica (GPC) Publicaciones incluidas en la sección de descripción y evaluación: Neunert et al., 2021. "American Society of Hematology 2019 guidelines for immune thrombocytopenia" (Cindy Neunert et al. 2019). Provan et al., 2019. "Updated international consensus report on the investigation and management of primary immune thrombocytopenia" (Provan et al. 2019). Publicaciones No incluidas en la sección de descripción y evaluación: La siguiente GPC no fue incluida dentro de la evidencia del presente dictamen porque no brinda recomendaciones para la población objetivo del presente dictamen (pacientes con intolerancia a un primer TPO-RA y no candidatos a esplenectomía). Centro Nacional de Excelencia Tecnológica en Salud (CENETEC). "Diagnóstico y Tratamiento de Trombocitopenia Inmune Primaria" (CENETEC 2019). La siguiente GPC no fue incluida en la evidencia del presente dictamen porque los autores no realizaron una búsqueda sistemática de la evidencia para formular sus recomendaciones. Matzdorff et al., 2018. "Immune Thrombocytopenia - Current Diagnostics and Therapy: Recommendations of a Joint Working Group of DGHO, OGHO, SGH, GPOH, and DGTI" (Matzdorff et al. 2018). La siguiente GPC no fue incluida dentro de la evidencia del presente dictamen porque se encuentra disponible una versión más actualizada de la guía. Neunert et al., 2011. "The American Society of Hematology 2011 evidencebased practice guideline for immune thrombocytopenia" (Cindy Neunert et al. 2011). CONCLUSIONES: En el presente dictamen, se evaluó la mejor evidencia científica, disponible hasta la actualidad, en relación con la eficacia y seguridad de romiplostim en pacientes pediátricos con trombocitopenia inmune primaria crónica, respuesta inadecuada o intolerancia a inmunoglobulina, corticoesteroides e intolerancia a eltrombopag, no candidatos a esplenectomía. La búsqueda sistemática de la evidencia culminó con la selección de una GPC (Provan et al. 2019). También, se analizó la GPC de la ASH, que fue sugerida por los especialistas de EsSalud (Cindy Neunert et al. 2019). Además, debido a que no se encontraron estudios que evaluaran el uso de romiplostim versus corticoesteroides o inmunoglobulina, se analizaron los resultados del ECA de fase III, pivotal de romiplostim (Tarantino et al. 2016). La GPC de la ASH no brinda recomendaciones para pacientes que hayan recibido previamente un TPO-RA, característica de la población de interés para el presente dictamen. El reporte de consenso de Provan et al. recomienda, basada en la experiencia/opinión de expertos, cambiar a un TPO-RA alternativo y/o considerar combinarlo con inmunosupresores, en pacientes en los que no hay respuesta a un TPO-RA o se pierde la respuesta. El ECA de Tarantino et al., pivotal de romiplostim, que compara el uso de romiplostim versus placebo, muestra que romiplostim generaría un beneficio en términos de la respuesta plaquetaria duradera y respuesta plaquetaria general. No se observaron diferencias en la incidencia de episodios de sangrado serio y EA serios, calidad de vida y el uso de medicamentos de rescate. Los especialistas de EsSalud señalan que los pacientes pediátricos con TPI y conteo de plaquetas menores de 10 x 109/L tienen un mayor riesgo de sangrado serio (i.e hemorragias intracraneales). En línea con esto, en la literatura se indica que un conteo plaquetas menor de 10 x 109/L o 20 x 109/L es un predictor de sangrado serio. En el ECA de Tarantino et al., pivotal de romiplostim, la mitad de los participantes que recibieron romiplostim tuvieron un conteo basal de plaquetas menor de 20 x 109/L; por lo que es plausible que la respuesta plaquetaria producida con el uso de romiplostim sí reduzca el riesgo de sangrado serio en aquellos pacientes cuyo conteo de plaquetas es menor de 10 x 109/L o de 20 x 109/L. Por todo lo expuesto, el 'ETS' aprueba el uso de romiplostim en pacientes pediátricos con trombocitopenia inmune primaria crónica; respuesta inadecuada o intolerancia a inmunoglobulina, corticoesteroides; intolerancia a eltrombopag; no candidatos a esplenectomía, y conteo de plaquetas menor de 20 x 109/L a pesar del tratamiento, según lo establecido en el Anexo N°1. Debido a la incertidumbre sobre el balance riesgo-beneficio, no se aprueba el uso de romiplostim en los pacientes con conteo de plaquetas mayor o igual a 20 x 109/L. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.
Assuntos
Humanos , Pré-Escolar , Criança , Trombocitopenia/tratamento farmacológico , Imunoglobulinas/efeitos adversos , Corticosteroides/efeitos adversos , Fator G para Elongação de Peptídeos/agonistas , Receptores de Trombopoetina/agonistas , Doenças do Sistema Imunitário/tratamento farmacológico , Eficácia , Análise Custo-Benefício/economiaRESUMO
PDZ (postsynaptic density (PSD95), discs large (Dlg), and zonula occludens (ZO-1)-dependent interactions are widely distributed within different cell types and regulate a variety of cellular processes. To date, some of these interactions have been identified as targets of small molecules or peptides, mainly related to central nervous system disorders and cancer. Recently, the knowledge of PDZ proteins and their interactions has been extended to various cell types of the immune system, suggesting that their targeting by viral pathogens may constitute an immune evasion mechanism that favors viral replication and dissemination. Thus, the pharmacological modulation of these interactions, either with small molecules or peptides, could help in the control of some immune-related diseases. Deeper structural and functional knowledge of this kind of protein-protein interactions, especially in immune cells, will uncover novel pharmacological targets for a diversity of clinical conditions.
Assuntos
Domínios PDZ/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/metabolismo , Modelos Moleculares , Terapia de Alvo Molecular , Peptídeos/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.
Assuntos
Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/metabolismo , Lisofosfolipídeos/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Preparações Farmacêuticas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Humanos , Esfingosina/metabolismoRESUMO
Histone Deacetylase- (HDAC-) dependent epigenetic mechanisms have been widely explored in the last decade in different types of malignancies in preclinical studies. This effort led to the discovery and development of a range of new HDAC inhibitors (iHDAC) with different chemical properties and selective abilities. In fact, hematological malignancies were the first ones to have new iHDACs approved for clinical use, such as Vorinostat and Romidepsin for cutaneous T cell lymphoma and panobinostat for multiple myeloma. Besides these promising already approved iHDACs, we highlight a range of studies focusing on the HDAC-dependent epigenetic control of B cell development, behavior, and/or function. Here, we highlight 21 iHDACs which have been studied in the literature in the context of B cell development and/or dysfunction mostly focused on B cell lymphomagenesis. Regardless, we have identified 55 clinical trials using 6 out of 21 iHDACs to approach their putative roles on B cell malignancies; none of them focuses on peritoneal B cell populations. Since cells belonging to this peculiar body compartment, named B1 cells, may contribute to the development of autoimmune pathologies, such as lupus, a better understanding of the HDAC-dependent epigenetic mechanisms that control its biology and behavior might shed light on iHDAC use to manage these immunological dysfunctions. In this sense, iHDACs might emerge as a promising new approach for translational studies in this field. In this review, we discuss a putative role of iHDACs in the modulation of peritoneal B cell subpopulation's balance as well as their role as therapeutic agents in the context of chronic diseases mediated by peritoneal B cells.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Epigênese Genética , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/metabolismo , Imunomodulação , Terapia de Alvo Molecular , Animais , Linfócitos B/efeitos dos fármacos , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Cavidade Peritoneal/citologia , Cavidade Peritoneal/patologia , Pesquisa Translacional BiomédicaRESUMO
BACKGROUND: In Brazil, we are facing an alarming epidemic scenario of Yellow fever (YF), which is reaching the most populous areas of the country in unvaccinated people. Vaccination is the only effective tool to prevent YF. In special situations, such as patients with chronic immune-mediated inflammatory diseases (CIMID), undergoing immunosuppressive therapy, as a higher risk of severe adverse events may occur, assessment of the risk-benefit ratio of the yellow fever vaccine (YFV) should be performed on an individual level. Faced with the scarcity of specific orientation on YFV for this special group of patients, the Brazilian Rheumatology Society (BRS) endorsed a project aiming the development of individualized YFV recommendations for patients with CIMID, guided by questions addressed by both medical professionals and patients, followed an internationally validated methodology (GIN-McMaster Guideline Development). Firstly, a systematic review was carried out and an expert panel formed to take part of the decision process, comprising BRS clinical practitioners, as well as individuals from the Brazilian Dermatology Society (BDS), Brazilian Inflammatory Bowel Diseases Study Group (GEDIIB), and specialists on infectious diseases and vaccination (from Tropical Medicine, Infectious Diseases and Immunizations National Societies); in addition, two representatives of patient groups were included as members of the panel. When the quality of the evidence was low or there was a lack of evidence to determine the recommendations, the decisions were based on the expert opinion panel and a Delphi approach was performed. A recommendation was accepted upon achieving ≥80% agreement among the panel, including the patient representatives. As a result, eight recommendations were developed regarding the safety of YFV in patients with CIMID, considering the immunosuppression degree conferred by the treatment used. It was not possible to establish recommendations on the effectiveness of YFV in these patients as there is no consistent evidence to support these recommendations. CONCLUSION: This paper approaches a real need, assessed by clinicians and patient care groups, to address specific questions on the management of YFV in patients with CIMID living or traveling to YF endemic areas, involving specialists from many areas together with patients, and might have global applicability, contributing to and supporting vaccination practices. We recommended a shared decision-making approach on taking or not the YFV.
Assuntos
Doenças do Sistema Imunitário/tratamento farmacológico , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Inflamação/tratamento farmacológico , Vacina contra Febre Amarela/efeitos adversos , Febre Amarela/prevenção & controle , Doença Crônica , Contraindicações de Medicamentos , Tomada de Decisão Compartilhada , Técnica Delphi , Humanos , Doenças do Sistema Imunitário/imunologia , Inflamação/imunologia , Medição de Risco , Vacinação/efeitos adversos , Vacina contra Febre Amarela/administração & dosagemRESUMO
BACKGROUND: Little clinical information is available concerning the use of leflunomide in dogs with immune-mediated diseases. OBJECTIVES: To report the safety and efficacy of leflunomide for the treatment of naturally occurring immune-mediated diseases in dogs. ANIMALS: Ninety-two dogs treated with leflunomide for management of suspected immune-mediated diseases. METHODS: Retrospective medical record review from Jan 1995 to Dec 2014. Data that were extracted from the medical records included signalment, body weight, underlying indication for leflunomide, dosage of leflunomide, treatment duration, concurrent medications, treatment response, and adverse events. RESULTS: Adverse events that could be related to leflunomide administration included diarrhea (3 of 92, 3.3%), lethargy (2 of 92, 2.2%), unexplained hemorrhage (3 of 92, 3.3%), thrombocytopenia (2 of 31, 6.5%), and increased liver enzyme activities (1 of 16, 6.3%). Significant dose differences between dogs with adverse events (n = 11; median, 2.9 mg/kg/d; range, 1.8-3.6 mg/kg/d) and dogs without adverse events (n = 81; median, 1.6 mg/kg/d; range, 0.8-4.3 mg/kg/d) were found (P < 0.001). Treatment response could be evaluated in 17 dogs. Of these 17 dogs, 12 dogs (70.5%) had an apparent positive response to the use of leflunomide. There was no significant difference (P = 0.22) in dosages between dogs that responded to leflunomide (n = 12; median, 1.9 mg/kg/d; range, 1.0-3.5 mg/kg/d) and those that did not respond (n = 5; median, 1.7 mg/kg/d; range, 1.0-2.0 mg/kg/d). CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that the starting dosage of leflunomide should be 2 mg/kg/d rather than the currently suggested dosage of 3-4 mg/kg/d.
Assuntos
Doenças do Cão/tratamento farmacológico , Doenças do Sistema Imunitário/veterinária , Imunossupressores/uso terapêutico , Isoxazóis/uso terapêutico , Animais , Doenças do Cão/imunologia , Cães , Feminino , Doenças do Sistema Imunitário/tratamento farmacológico , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Leflunomida , Masculino , Estudos RetrospectivosRESUMO
Haem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC- and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases.
Assuntos
Apresentação de Antígeno , Heme Oxigenase-1/metabolismo , Doenças do Sistema Imunitário/tratamento farmacológico , Tolerância Imunológica , Inflamação/metabolismo , Linfócitos T/imunologia , Animais , Monóxido de Carbono/metabolismo , Desenho de Fármacos , Humanos , Imunomodulação , Ativação LinfocitáriaRESUMO
Inflammation is a local tissue response to attacks characterized by vascular and cellular events, including intense oxidative stress. Riparin A, a compound obtained from Aniba riparia, has been shown to have antioxidant activity and cytotoxicity in vitro. This study was aimed at evaluating the anti-inflammatory effect of riparin A against acute inflammation. The results of our evaluations in various experimental models indicated that riparin A reduced paw edema induced by carrageenan, compound 48/80, histamine, and serotonin. Furthermore, it decreased leukocyte and neutrophil counts, myeloperoxidase activity, thiobarbituric acid reactive substance (TBARS) levels, and cytokine (tumor necrosis factor-α and interleukin-1ß) levels increased by carrageenan-induced peritonitis, and reversed glutathione levels. Riparin A also reduced carrageenan-induced adhesion and rolling of leukocytes on epithelial cells and did not produce gastric-damage as compared with indomethacin. In conclusion, the data show that riparin A reduces inflammatory response by inhibiting vascular and cellular events, modulating neutrophil migration, inhibiting proinflammatory cytokine production, and reducing oxidative stress.
Assuntos
Anti-Inflamatórios/uso terapêutico , Benzamidas/uso terapêutico , Carragenina/efeitos adversos , Edema/tratamento farmacológico , Doenças do Sistema Imunitário/tratamento farmacológico , Transtornos Leucocíticos/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Peritonite/tratamento farmacológico , Fenetilaminas/uso terapêutico , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , Benzamidas/isolamento & purificação , Carragenina/imunologia , Adesão Celular/efeitos dos fármacos , Citocinas/imunologia , Edema/induzido quimicamente , Edema/imunologia , Edema/patologia , Extremidades/patologia , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Lauraceae/química , Transtornos Leucocíticos/induzido quimicamente , Transtornos Leucocíticos/imunologia , Transtornos Leucocíticos/patologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/imunologia , Neutrófilos/patologia , Estresse Oxidativo/efeitos dos fármacos , Peritonite/induzido quimicamente , Peritonite/imunologia , Peritonite/patologia , Peroxidase/imunologia , Fenetilaminas/isolamento & purificaçãoRESUMO
AIMS: The present study aimed to investigate the potential anti-inflammatory and anti-nociceptive effects of carvacryl acetate, a derivative of carvacrol, in mice. MAIN METHODS: The anti-inflammatory activity was evaluated using various phlogistic agents that induce paw edema, peritonitis model, myeloperoxidase (MPO) activity, pro and anti-inflammatory cytokine levels. Evaluation of antinociceptive activity was conducted through acetic acid-induced writhing, hot plate test, formalin test, capsaicin and glutamate tests, as well as evaluation of motor performance on rotarod test. KEY FINDINGS: Pretreatment of mice with carvacryl acetate (75 mg/kg) significantly reduced carrageenan-induced paw edema (P<0.05) when compared to vehicle-treated group. Likewise, carvacryl acetate (75 mg/kg) strongly inhibited edema induced by histamine, serotonin, prostaglandin E2 and compound 48/80. In the peritonitis model, carvacryl acetate significantly decreased total and differential leukocyte counts, and reduced levels of myeloperoxidase and interleukin-1 beta (IL-1ß) in the peritoneal exudate. The levels of IL-10, an anti-inflammatory cytokine, were enhanced by carvacryl acetate. Pretreatment with carvacryl acetate also decreased the number of acetic acid-induced writhing, increased the latency time of the animals on the hot plate and decreased paw licking time in the formalin, capsaicin and glutamate tests. The pretreatment with naloxone did not reverse the carvacryl acetate-mediated nociceptive effect. SIGNIFICANCE: In conclusion, the current study demonstrated that carvacryl acetate exhibited anti-inflammatory activity in mice by reducing inflammatory mediators, neutrophil migration and cytokine concentration, and anti-nociceptive activity due to the involvement of capsaicin and glutamate pathways.