RESUMEN

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Cannabidiol/farmacología , Cognición/efectos de los fármacos , Interleucina-33/efectos de los fármacos , Glicoproteínas de Membrana/efectos de los fármacos , Receptores Inmunológicos/efectos de los fármacos , Enfermedad de Alzheimer/patología , Animales , Modelos Animales de Enfermedad , Humanos , Interleucina-33/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Transgénicos , Receptores Inmunológicos/metabolismo , Regulación hacia Arriba

RESUMEN

Introduction: Triggering receptors expressed on myeloid cells (TREMs) are inflammatory amplifiers with defined pathophysiological role in various infectious diseases, acute and chronic aseptic inflammations, and a variety of cancers, depicting TREMs as prominent therapeutic targets.Areas covered: Herein, updates from 2015 to 2020 are discussed to divulge the TREM ligands, as well as their peptide blockers, claimed to modulate their expression. The article also presents different strategies employed during the last five years to block interactions between TREMs and their ligands to treat various disease conditions by modulating their expression and activity.Expert opinion: There has been significant progress in the discovery of novel ligands and modulators of TREMs in the last five years that mainly revolved around the function of TREM molecules. A few peptides showed encouraging results to modulate the expression and activity of TREMs in preclinical studies, and these peptides are currently under clinical investigation. Based on the findings so far in several careful studies, we expect novel therapeutics in the near future which could have the ability to treat various disease conditions associated with TREM expression.

Asunto(s)

Glicoproteínas de Membrana/efectos de los fármacos , Terapia Molecular Dirigida , Receptores Inmunológicos/efectos de los fármacos , Receptor Activador Expresado en Células Mieloides 1/efectos de los fármacos , Animales , Desarrollo de Medicamentos , Descubrimiento de Drogas , Humanos , Ligandos , Glicoproteínas de Membrana/metabolismo , Patentes como Asunto , Receptores Inmunológicos/metabolismo , Receptor Activador Expresado en Células Mieloides 1/metabolismo

Asunto(s)

Antipsicóticos/uso terapéutico , Delirio/tratamiento farmacológico , Infecciones por VIH , Haloperidol/uso terapéutico , Antígenos CD/efectos de los fármacos , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacología , Delirio/patología , Proteínas Ligadas a GPI/efectos de los fármacos , Haloperidol/administración & dosificación , Haloperidol/farmacología , Humanos , Receptores Inmunológicos/efectos de los fármacos

Asunto(s)

Betacoronavirus/efectos de los fármacos , Integrinas/uso terapéutico , Receptores Virales/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/efectos de los fármacos , Sitios de Unión , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Humanos , Pandemias , Neumonía Viral/tratamiento farmacológico , Receptores Inmunológicos/efectos de los fármacos , Receptores de Péptidos/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Internalización del Virus/efectos de los fármacos , Tratamiento Farmacológico de COVID-19

RESUMEN

OBJECTIVE: A number of studies have demonstrated that molecules called 'alarmins' or danger-associated molecular patterns (DAMPs), contribute to inflammatory processes in the OA joint. Metabolic reprogramming of immune cells, including macrophages, is emerging as a prominent player in determining immune cell phenotype and function. The aim of this study was to investigate if basic calcium phosphate (BCP) crystals which are OA-associated DAMPs, impact on macrophage phenotype and metabolism. METHODS: Human monocyte derived macrophages were treated with BCP crystals and expression of M1 (CXCL9, CXCL10) and M2 (MRC1, CCL13)-associated markers was assessed by real-time PCR while surface maturation marker (CD40, CD80 & CD86) expression was assessed by flow cytometry. BCP induced metabolic changes were assessed by Seahorse analysis and glycolytic marker expression (hexokinase 2(HK2), Glut1 and HIF1α) was examined using real-time PCR and immunoblotting. RESULTS: Treatment with BCP crystals upregulated mRNA levels of CXCL9 and CXCL10 while concomitantly downregulating expression of CCL13 and MRC1. Furthermore, BCP-treated macrophages enhanced surface expression of the maturation makers, CD40, CD80 and CD86. BCP-treated cells also exhibited a shift towards glycolysis as evidenced by an increased ECAR/OCR ratio and enhanced expression of the glycolytic markers, HK2, Glut1 and HIF1α. Finally, BCP-induced macrophage activation and alarmin expression was reduced in the presence of the glycolytic inhibitor, 2-DG. CONCLUSIONS: This study not only provides further insight into how OA-associated DAMPs impact on immune cell function, but also highlights metabolic reprogramming as a potential therapeutic target for calcium crystal-related arthropathies.

Asunto(s)

Fosfatos de Calcio/farmacología , Citocinas/efectos de los fármacos , Glucólisis/efectos de los fármacos , Macrófagos/efectos de los fármacos , Osteoartritis/inmunología , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD40/metabolismo , Quimiocina CXCL10/efectos de los fármacos , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Quimiocina CXCL9/efectos de los fármacos , Quimiocina CXCL9/genética , Quimiocina CXCL9/inmunología , Citocinas/genética , Regulación hacia Abajo , Transportador de Glucosa de Tipo 1/efectos de los fármacos , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Glucólisis/genética , Hexoquinasa/efectos de los fármacos , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Glicoproteínas de Membrana/efectos de los fármacos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Proteínas Quimioatrayentes de Monocitos/efectos de los fármacos , Proteínas Quimioatrayentes de Monocitos/genética , Proteínas Quimioatrayentes de Monocitos/inmunología , Osteoartritis/genética , Fenotipo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Inmunológicos/efectos de los fármacos , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Regulación hacia Arriba

RESUMEN

Dendritic cells (DC), which are involved in orchestrating early immune responses against pathogens, are dysregulated in their function by HIV infection. This dysregulation likely contributes to tip the balance toward viral persistence. Different DC subpopulations, including classical (cDCs) and plasmacytoid (pDCs) dendritic cells, are subjected to concomitant inflammatory and immunoregulatory events during HIV infection, which hampers the precise characterization of their regulation through classical approaches. Here, we carried out mass cytometry analysis of blood samples from early HIV-infected patients that were longitudinally collected before and after 1 year of effective combination antiretroviral therapy (cART). Blood samples from HIV controller patients who naturally control the infection were also included. Our data revealed that plasma HIV RNA level was positively associated with a loss of cDC and pDC subpopulations that display high expression of LILR immunomodulatory receptors. Conversely, specific monocyte populations co-expressing high levels of HLA-I, 3 immunomodulatory receptors, CD64, LILRA2, and LILRB4, and the restriction factor CD317 (also known as BST2/Tetherin), were more abundant in early HIV-infection. Finally, our analysis revealed that the blood of HIV controller patients contained in a higher abundance a particular subtype of CD1c+ cDCs, characterized by elevated co-expression of CD32b inhibitory receptor and HLA-DR antigen-presentation molecules. Overall, this study unravels the modifications induced in DC and monocyte subpopulations in different HIV+ conditions, and provides a better comprehension of the immune regulation/dysregulation mechanisms induced during this viral infection.

Asunto(s)

Células Dendríticas/inmunología , Infecciones por VIH/inmunología , Monocitos/inmunología , Adulto , Fármacos Anti-VIH/uso terapéutico , Células Dendríticas/efectos de los fármacos , Femenino , Citometría de Flujo , Infecciones por VIH/tratamiento farmacológico , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Receptores Inmunológicos/efectos de los fármacos , Receptores Inmunológicos/inmunología

RESUMEN

This study tested whether brain L-PGDS (lipocalin-type prostaglandin [PG] D synthase), through prostanoid signaling, might increase neurogenic pressor activity and thereby cause hypertension. Sprague Dawley rats on high-salt diet received either vehicle or Ang II (angiotensin II) infusion. On day 4, the developmental stage of hypertension, brains from different sets of control and Ang II-treated rats were collected for measuring L-PGDS expression, PGD2 levels, and DP1R (type 1 PGD2 receptor) expression. In a different set of 14-day Ang II-salt-treated rats, mini-osmotic pumps were used to infuse either a nonselective COX (cyclooxygenase) inhibitor ketorolac, L-PGDS inhibitor AT56, or DP1R inhibitor BWA868C to test the role of brain COX-PGD2-DP1R signaling in Ang II-salt hypertension. The acute depressor response to ganglion blockade with hexamethonium was used to quantify neurogenic pressor activity. During the developmental stage of Ang II-salt hypertension, L-PGDS expression was higher in cerebrospinal fluid, and PGD2 levels were increased in the choroid plexus, cerebrospinal fluid, and the cardioregulatory brain region rostral ventrolateral medulla. DP1R expression was decreased in rostral ventrolateral medulla. Both brain COX inhibition with ketorolac and L-PGDS inhibition with AT56 lowered mean arterial pressure by altering neurogenic pressor activity compared with vehicle controls. Blockade of DP1R with BWA868C, however, increased the magnitude of Ang II-salt hypertension and significantly increased neurogenic pressor activity. In summary, we establish that the development of Ang II-salt hypertension requires increased COX- and L-PGDS-derived PGD2 production in the brain, making L-PGDS a possible target for treating neurogenic hypertension.

Asunto(s)

Angiotensina II/farmacología , Presión Arterial/fisiología , Encéfalo/diagnóstico por imagen , Hipertensión/fisiopatología , Ketorolaco/farmacología , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Animales , Presión Arterial/efectos de los fármacos , Biomarcadores/sangre , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cromatografía Liquida/métodos , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores Inmunológicos/efectos de los fármacos , Receptores de Prostaglandina/efectos de los fármacos , Valores de Referencia , Medición de Riesgo , Cloruro de Sodio Dietético/administración & dosificación , Cloruro de Sodio Dietético/metabolismo , Espectrometría de Masas en Tándem/métodos

RESUMEN

Apoptosis following hypoxic-ischemic injury to the brain plays a major role in neuronal cell death. The neonatal brain is more susceptible to injury as the cortical neurons are immature and there are lower levels of antioxidants. Slit2, an extracellular matrix protein, has been shown to be neuroprotective in various models of neurological diseases. However, there is no information about the role of Slit2 in neonatal hypoxia-ischemia. In this study, we evaluated the effect of Slit2 and its receptor Robo1 in a rat model with neonatal HIE. 10-day old rat pups were used to create the neonatal HIE model. The right common carotid artery was ligated followed by 2.5 h of hypoxia. Recombinant Slit2 was administered intranasally 1 h post HI, recombinant Robo1 was used as a decoy receptor and administered intranasally 1h before HI and srGAP1-siRNA was administered intracerebroventricularly 24 h before HI. Brain infarct area measurement, short-term and long-term neurological function tests, Western blot, immunofluorescence staining, Fluoro-Jade C staining, Nissl staining and TUNEL staining were the assessments done following drug administration. Recombinant Slit2 administration reduced neuronal apoptosis and neurological deficits after neonatal HIE which were reversed by co-administration of recombinant Robo1 and srGAP1-siRNA administration. Recombinant Slit2 showed improved outcomes possibly via the robo1-srGAP1 pathway which mediated the inhibition of RhoA. In this study, the results suggest that Slit2 may help in attenuation of apoptosis and could be a therapeutic agent for treatment of neonatal hypoxic ischemic encephalopathy.

Asunto(s)

Apoptosis/efectos de los fármacos , Proteínas Activadoras de GTPasa/efectos de los fármacos , Hipoxia-Isquemia Encefálica/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/farmacología , Proteínas del Tejido Nervioso/efectos de los fármacos , Proteínas del Tejido Nervioso/farmacología , Neuronas/efectos de los fármacos , Receptores Inmunológicos/efectos de los fármacos , Administración Intranasal , Animales , Animales Recién Nacidos , Proteínas Activadoras de GTPasa/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , Etiquetado Corte-Fin in Situ , Inyecciones Intraventriculares , Proteínas del Tejido Nervioso/metabolismo , ARN Interferente Pequeño , Ratas , Receptores Inmunológicos/metabolismo , Proteínas Recombinantes , Transducción de Señal , Proteínas de Unión al GTP rho/efectos de los fármacos , Proteínas de Unión al GTP rho/metabolismo , Proteínas Roundabout

RESUMEN

Among the main promising systems to triggering therapeutic antitumor immunity is the blockade of immune checkpoints. Immune checkpoint pathways regulate the control and eradication of infections, malignancies, and resistance against a host of autoantigens. Initiation point of the immune response is T cells, which have a critical role in this pathway. As several immune checkpoints are initiated by ligand-receptor interactions, they can be freely blocked by antibodies or modulated by recombinant forms of ligands or receptors. Antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) were the first immunotherapeutics that achieved the US Food and Drug Administration approval. Preliminary clinical results with the blockers of additional immune checkpoint proteins, such as programmed cell death protein 1 (PD-1) indicate extensive and different chances to boost antitumor immunity with the objective of conferring permanent clinical effects. This study provides an overview of the immune checkpoint pathways, including CTLA-4, PD-1, lymphocyte activation gene 3, T-cell immunoglobulin and mucin domain 3, B7-H3, and diacylglycerol kinase α and implications of their inhibition in the cancer therapy.

Asunto(s)

Antineoplásicos Inmunológicos/uso terapéutico , Inmunoterapia , Neoplasias/tratamiento farmacológico , Receptores Inmunológicos/efectos de los fármacos , Animales , Antineoplásicos Inmunológicos/efectos adversos , Resistencia a Antineoplásicos , Humanos , Inmunoterapia/efectos adversos , Terapia Molecular Dirigida , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Transducción de Señal , Microambiente Tumoral

RESUMEN

Hepatitis B virus (HBV) infection affects approximately 300 million people worldwide. Although antiviral therapies have improved the long-term outcomes, patients often require life-long treatment and there is no cure for HBV infection. New technologies can help us learn more about the pathogenesis of HBV infection and develop therapeutic agents to reduce its burden. We review recent advances in development of direct-acting antiviral and host-targeting agents, some of which have entered clinical trials. We also discuss strategies for unbiased high-throughput screens to identify compounds that inhibit HBV and for repurposing existing drugs.

Asunto(s)

Antivirales/farmacología , Desarrollo de Medicamentos , Hepatitis B/terapia , Cápside/efectos de los fármacos , Humanos , Factores Inmunológicos/farmacología , Receptores Inmunológicos/efectos de los fármacos , Receptores Virales/efectos de los fármacos , Replicación Viral/efectos de los fármacos

RESUMEN

T lymphocytes have a crucial role in initiating and promoting type I allergies. Their responses are tightly regulated by numerous activating and inhibitory signals provided by APCs. Here we have addressed the role of the major coinhibitory receptors PD-1, CTLA-4, BTLA and LAG-3 in allergen-specific CD4+ T cell responses. PBMCs of healthy individuals and 41 patients allergic to house dust mites, birch, grass or mugwort pollen were stimulated with allergenic extracts and expression of coinhibitory receptors on responding CD4+ T cells was assessed. Blocking antibodies to PD-1, CTLA-4, BTLA and LAG-3 were used to evaluate the role of coinhibitory pathways. Allergen-specific CD4+ T cells showed strong upregulation of PD-1, LAG-3 and CTLA-4 upon stimulation, whereas BTLA was downregulated. Blockade of PD-1 strongly enhanced proliferation and cytokine production (IL-10; TH1 cytokines IFN-γ, TNF-α; TH2 cytokines IL-5, IL-13) of allergen-specific CD4+ T cells derived from allergic as well as non-allergic individuals. BTLA blockade enhanced proliferation but not cytokine production in response to house dust mite extract. Blocking LAG-3 was ineffective and surprisingly, we observed reduced proliferation and cytokine production in presence of a CTLA-4 antibody. Our results point to a unique potency of PD-1 pathways to dampen allergen-specific human T cells.

Asunto(s)

Alérgenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Hipersensibilidad/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal/inmunología , Adulto , Antígenos CD/efectos de los fármacos , Antígenos CD/inmunología , Antígenos CD/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/efectos de los fármacos , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Proliferación Celular/efectos de los fármacos , Estudios de Cohortes , Citocinas/inmunología , Citocinas/metabolismo , Regulación hacia Abajo/inmunología , Femenino , Voluntarios Sanos , Humanos , Hipersensibilidad/sangre , Hipersensibilidad/tratamiento farmacológico , Activación de Linfocitos , Masculino , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/efectos de los fármacos , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/inmunología , Proteína del Gen 3 de Activación de Linfocitos

RESUMEN

Immunomodulatory protein hydrolysate consumption may delay or prevent western immune-related diseases. In order to purposively develop protein hydrolysates with an optimal and reproducible immunomodulatory effect, knowledge is needed on which components in protein hydrolysates are responsible for the immune effects. Important advances have been made on this aspect. Also, knowledge on mechanisms underlying the immune modulating effects is indispensable. In this review, we discuss the most promising application possibilities for immunomodulatory protein hydrolysates. In order to do so, an overview is provided on reported in vivo immune effects of protein hydrolysates in both local intestinal and systemic organs, and the current insights in the underlying mechanisms of these effects. Furthermore, we discuss current knowledge and physicochemical approaches to identify the immune active protein sequence(s). We conclude that multiple hydrolysate compositions show specific immune effects. This knowledge can improve the efficacy of existing hydrolysate-containing products such as sports nutrition, clinical nutrition, and infant formula. We also provide arguments for why immunomodulatory protein hydrolysates could be applied to manage the immune response in the increasing number of individuals with a higher risk of immune dysfunction due to, for example, increasing age or stress.

Asunto(s)

Suplementos Dietéticos , Sistema Inmunológico/efectos de los fármacos , Factores Inmunológicos/administración & dosificación , Hidrolisados de Proteína/administración & dosificación , Animales , Suplementos Dietéticos/efectos adversos , Endocitosis , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunidad Mucosa/efectos de los fármacos , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/inmunología , Factores Inmunológicos/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Intestinos/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Transportador de Péptidos 1/metabolismo , Hidrolisados de Proteína/efectos adversos , Hidrolisados de Proteína/inmunología , Hidrolisados de Proteína/metabolismo , Receptores Inmunológicos/efectos de los fármacos , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo

RESUMEN

BACKGROUND & OBJECTIVE: Epilepsy is one of the most complex neurological disorders and its study requires a broad knowledge of neurology and neuroscience. It comprises a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures, and are often accompanied by cognitive deficits and mood disorder. This condition is one of the most common neurological disorders. Until recently, alterations of neuronal activities had been the focus of epilepsy research. This neurocentric emphasis did not address issues that arise in more complex models of epileptogenesis. An important factor in epilepsy that is not regulated directly by neurons is inflammation and the immune response of the brain. Recent evidence obtained in rodent epilepsy models supports the role of immune responses in the initiation and maintenance of epilepsy. Recognition of exogenous pathogens by the innate immune system is mediated by some pattern recognition receptors such as Toll-like receptors leading to cell activation and cytokine production. Currently, these receptors have been the focus of epilepsy studies looking to determine whether the innate immune activation is neuroprotective or neurotoxic for the brain. CONCLUSION: Here, we present the evidence in the literature of the involvement of key innate immune receptors in the development of epilepsy. We address some of the contradictory findings in these studies and also mention possible avenues for research into epilepsy treatments that target these receptors.

Asunto(s)

Epilepsia/fisiopatología , Inmunidad Innata/fisiología , Receptores Inmunológicos/fisiología , Animales , Humanos , Terapia Molecular Dirigida/métodos , Receptores Inmunológicos/efectos de los fármacos

RESUMEN

The antimicrobial function of neutrophils, which is dependent on opsonin receptors, deteriorates in severe acute pancreatitis (SAP). Granulocyte colony-stimulating factor (G-CSF) putatively enhanced levels of the opsonin receptors CD11b and CD32/16 in healthy human subjects, and provided protection against infection in animal models of SAP. A statistically convincing study of the effect of G-CSF on CD32/16 expression in an SAP model is lacking. We used a mouse model of SAP to investigate the association between G-CSF administration and CD32/16 levels on neutrophils and bacterial translocation. G-CSF or saline was subcutaneously injected into SAP-induced mice. The pancreases were histologically examined, and leukocytes were stained to count neutrophils. The expression of CD11b and CD32/16 on neutrophils was measured by flow cytometry, and bacterial translocation was observed by bacterial culture. The numbers of CD11b and CD32/16-positive neutrophils were significantly elevated in the SAP mice treated with G-CSF, and the mean fluorescence intensities of these receptors on neutrophils were significantly elevated. Bacterial translocations to cavity organs were suppressed from 17% to 6% by G-CSF treatment. Our results indicated that the number of neutrophils significantly increased with increasing expression of CD11b and CD32/16 and their mean fluorescence intensities (MFIs). This inhibited bacterial translocation to other organs. These results are in accord with other studies in SAP dogs and SAP mice. Our findings suggest that G-CSF was effective in protecting against bacterial infection in SAP mice.

Asunto(s)

Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Activación Neutrófila/efectos de los fármacos , Pancreatitis/fisiopatología , Receptores Inmunológicos/efectos de los fármacos , Enfermedad Aguda , Animales , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/inmunología , Femenino , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos/farmacología , Ratones , Pancreatitis/tratamiento farmacológico , Pancreatitis/inmunología , Receptores Inmunológicos/genética

RESUMEN

Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.

Asunto(s)

Antiinflamatorios/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Mediadores de Inflamación/antagonistas & inhibidores , Riñón/efectos de los fármacos , Nefritis/tratamiento farmacológico , Receptores Inmunológicos/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Humanos , Mediadores de Inflamación/metabolismo , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Terapia Molecular Dirigida , Nefritis/inmunología , Nefritis/metabolismo , Nefritis/patología , Valor Predictivo de las Pruebas , Receptores Inmunológicos/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

We report pharmacokinetics, pharmacodynamics, and safety of a novel anti-CD28 domain antibody antagonist (lulizumab pegol) in healthy subjects following single- or multiple-dose administration. A minimal anticipated biological effect level approach was used to select a 0.01 mg starting dose for a single-ascending-dose (SAD), double-blind, first-in-human study. Part 1 included 9 intravenous (IV; 0.01-100 mg) and 3 subcutaneous (SC; 9-50 mg) doses or placebo. In part 2, a keyhole limpet hemocyanin (KLH) immunization was performed in 16 subjects/panel, who received 1 of 3 IV doses (9-100 mg) or placebo. In a double-blind, multiple-ascending-dose (MAD) study, subjects received SC lulizumab 6.25 mg every 2 weeks, 12.5 mg weekly, 37.5 mg weekly, or placebo. Among 180 treated subjects, 169 completed the studies. Peak concentrations and areas under the curve from time 0 to infinity increased dose proportionally. Estimated SC bioavailability was 68.2%. Receptor occupancy of approximately ≥80% was maintained for ≥2 weeks at ≥9-mg doses (SAD) and throughout the dosing interval (MAD). IV doses ≥9 mg inhibited antibody production against KLH for 2 weeks. No significant cytokine or immune cell changes were observed. No immunogenicity responses persisted, and there was no correlation to adverse events. Headache occurred in 21 SAD and 4 MAD subjects receiving lulizumab; in the MAD study 5 lulizumab subjects experienced infections. Lulizumab IV or SC was safe at all doses studied, without evidence of cytokine release.

Asunto(s)

Anticuerpos Bloqueadores/metabolismo , Antígenos CD28/inmunología , Polietilenglicoles/farmacocinética , Administración Intravenosa , Adolescente , Adulto , Anticuerpos/efectos adversos , Anticuerpos Bloqueadores/efectos adversos , Disponibilidad Biológica , Citocinas/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Cefalea/inducido químicamente , Voluntarios Sanos , Hemocianinas/inmunología , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Receptores Inmunológicos/efectos de los fármacos , Adulto Joven

RESUMEN

Triggering receptors expressed on myeloid cell-1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells. TREM-1 amplifies the inflammatory response. Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 enzyme, have anti-inflammatory properties. However, the effects of EETs on TREM-1 expression under inflammatory stimulation remain unclear. Therefore, inhibition of soluble epoxide hydrolase (sEH) with a highly selective inhibitor [1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, TPPU] was used to stabilize EETs. LPS was intratracheally injected into mice to induce pulmonary inflammation, after TPPU treatment for 3 h. Histological examination showed TPPU treatment-alleviated LPS-induced pulmonary inflammation. TPPU decreased TREM-1 expression, but not DAP12 or MyD88 expression. Murine peritoneal macrophages were challenged with LPS in vitro. We found that TPPU reduced LPS-induced TREM-1 expression in a dose-dependent manner, but not DAP12 or MyD88 expression. TPPU also decreased downstream signal from TREM-1, reducing pro-inflammatory cytokine TNF-α and IL-1ß mRNA expression. Furthermore, TPPU treatment inhibited IkB degradation in vivo and in vitro. Our results indicate that the inhibition of sEH suppresses LPS-induced TREM-1 expression and inflammation via inhibiting NF-kB activation in murine macrophage.

Asunto(s)

Epóxido Hidrolasas/antagonistas & inhibidores , Glicoproteínas de Membrana/metabolismo , Células Mieloides/metabolismo , FN-kappa B/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Células Cultivadas , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Proteínas I-kappa B/efectos de los fármacos , Proteínas I-kappa B/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Compuestos de Fenilurea/farmacología , Piperidinas/farmacología , Neumonía/tratamiento farmacológico , Receptores Inmunológicos/efectos de los fármacos , Solubilidad , Receptor Activador Expresado en Células Mieloides 1

RESUMEN

Phytohemagglutinin (PHA) isolated from the family of Phaseolus vulgaris beans is a promising agent against viral infection; however, it has not yet been demonstrated in vivo. We herein investigated this issue using Drosophila as a host. Adult flies were fed lectin approximately 12 h before they were subjected to a systemic viral infection. After a fatal infection with Drosophila C virus, death was delayed and survival was longer in flies fed PHA-P, a mixture of L4, L3E1, and L2E2, than in control unfed flies. We then examined PHA-L4, anticipating subunit L as the active form, and confirmed the protective effects of this lectin at markedly lower concentrations than PHA-P. In both experiments, lectin feeding reduced the viral load prior to the onset of fly death. Furthermore, we found a dramatic increase in the levels of the mRNAs of phagocytosis receptors in flies after feeding with PHA-L4 while a change in the levels of the mRNAs of antimicrobial peptides was marginal. We concluded that P. vulgaris PHA protects Drosophila against viral infection by augmenting the level of host immunity.

Asunto(s)

Dicistroviridae , Drosophila/efectos de los fármacos , Mitógenos/farmacología , Fitohemaglutininas/farmacología , Tasa de Supervivencia , Virosis/virología , Animales , Drosophila/genética , Drosophila/virología , Phaseolus , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores Inmunológicos/efectos de los fármacos , Receptores Inmunológicos/genética , Carga Viral/efectos de los fármacos

RESUMEN

(1) BACKGROUND: A growing body of literature suggest that polymorphisms (SNPs) from inflammation-related genes could possibly play a role in cytokine production and then interact with dietary n-3 fatty acids (FAs) to modulate inflammation. The aim of the present study was to test whether gene expression of selected inflammatory genes was altered following an n-3 PUFA supplementation and to test for gene-diet interactions modulating plasma inflammatory biomarker levels. (2) METHODS: 191 subjects completed a 6-week n-3 FA supplementation with 5 g/day of fish oil. Gene expression of TNF-α and IL6 was assessed in peripheral blood mononuclear cells (PBMCs) using the TaqMan technology. Genotyping of 20 SNPs from the TNF-LTA gene cluster, IL1ß, IL6 and CRP genes was performed. (3) RESULTS: There was no significant reduction of plasma IL-6, TNF-α and C-reactive protein (CRP) levels after the 6-week fish oil supplementation. TNF-α and IL6 were slightly overexpressed in PBMCs after the supplementation (fold changes of 1.05 ± 0.38 and 1.18 ± 0.49, respectively (n = 191)), but relative quantification (RQ) within the -0.5 to 2.0 fold are considered as nonbiologically significant. In a MIXED model for repeated measures adjusted for the effects of age, sex and BMI, gene by supplementation interaction effects were observed for rs1143627, rs16944, rs1800797, and rs2069840 on IL6 levels, for rs2229094 on TNF-α levels and for rs1800629 on CRP levels (p < 0.05 for all). (4) CONCLUSIONS: This study shows that a 6-week n-3 FA supplementation with 5 g/day of fish oil did not alter gene expression levels of TNF-α and IL6 in PBMCs and did not have an impact on inflammatory biomarker levels. However, gene-diet interactions were observed between SNPs within inflammation-related genes modulating plasma inflammatory biomarker levels.

Asunto(s)

Suplementos Dietéticos , Ácidos Grasos Omega-3/farmacología , Aceites de Pescado/farmacología , Inflamación/metabolismo , Interleucina-6/genética , Receptores Inmunológicos/genética , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Biomarcadores/sangre , Femenino , Aceites de Pescado/química , Expresión Génica , Interacción Gen-Ambiente , Humanos , Inflamación/sangre , Inflamación/dietoterapia , Interleucina-6/sangre , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos/sangre , Receptores Inmunológicos/efectos de los fármacos , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Adulto Joven

RESUMEN

Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis.

Asunto(s)

Neuronas/efectos de los fármacos , Prostaglandina D2/farmacología , Rinitis Alérgica/inducido químicamente , Ganglio del Trigémino/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Estimulación Eléctrica , Cobayas , Histamina/farmacología , Masculino , Ovalbúmina/inmunología , Técnicas de Placa-Clamp , Receptores Inmunológicos/efectos de los fármacos , Receptores de Prostaglandina/efectos de los fármacos , Rinitis Alérgica/fisiopatología , Rinitis Alérgica/psicología , Estornudo/efectos de los fármacos