RESUMEN
The exact etiology and mechanisms that trigger the development of type 1 diabetes mellitus (DM1) are not conclusively studied. However, there is increasing scientific evidence that damage to pancreatic islet cells (ß-cells) in genetically predisposed individuals is initiated by environmental factors. Currently, the main tactic of DM1 treatment at the stage of clinical manifestations is based on insulin replacement therapy. The introduction of modern insulin drugs and devices for its delivery, as well as continuous glucose monitoring systems into medical practice does not relieve patients from the need to take this hormone for life. Therefore, the development of methods to prevent DM1 remains the main task of diabetes research. The purpose of this article was to review current preventive strategies aimed at preventing or stopping the progression of DM1 in high-risk individuals. This article was prepared based on a review of current publications from the PubMed bibliographic database. The article discusses strategies targeting environmental triggers, methods to regulate the immune response using current cellular approaches and novel autoantigens, as well as off-target effects of the BCG vaccine and general principles of personalized prevention.
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Diabetes Mellitus Tipo 1 , Humanos , Autoantígenos/uso terapéutico , Glucemia , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/prevención & control , Insulina/uso terapéuticoRESUMEN
IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4+ plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8+ and CD4+ SLAMF7+ T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.
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Enfermedades Autoinmunes , Neoplasias de los Conductos Biliares , Colangitis Esclerosante , Colangitis , Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , Inmunoglobulina G , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Colangitis/etiología , Autoantígenos/uso terapéutico , Conductos Biliares IntrahepáticosRESUMEN
Adoptive T cell-receptor therapy (ACT) could represent a promising approach in the targeted treatment of epithelial ovarian cancer (EOC). However, the identification of suitable tumor-associated antigens (TAAs) as targets is challenging. We identified and prioritized TAAs for ACT and other immunotherapeutic interventions in EOC. A comprehensive list of pre-described TAAs was created and candidates were prioritized, using predefined weighted criteria. Highly ranked TAAs were immunohistochemically stained in a tissue microarray of 58 EOC samples to identify associations of TAA expression with grade, stage, response to platinum, and prognosis. Preselection based on expression data resulted in 38 TAAs, which were prioritized. Along with already published Cyclin A1, the TAAs KIF20A, CT45, and LY6K emerged as most promising targets, with high expression in EOC samples and several identified peptides in ligandome analysis. Expression of these TAAs showed prognostic relevance independent of molecular subtypes. By using a systematic vetting algorithm, we identified KIF20A, CT45, and LY6K to be promising candidates for immunotherapy in EOC. Results are supported by IHC and HLA-ligandome data. The described method might be helpful for the prioritization of TAAs in other tumor entities.
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Autoantígenos , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/terapia , Autoantígenos/uso terapéutico , Antígenos de Neoplasias , Neoplasias Ováricas/metabolismo , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, reflecting MuSK-specific B cell depletion. Specific off-target interactions of MuSK-CAART were not identified in vivo, in primary human cell screens or by high-throughput human membrane proteome array. These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.
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Miastenia Gravis Autoinmune Experimental , Receptores Colinérgicos , Humanos , Ratones , Animales , Receptores Colinérgicos/uso terapéutico , Autoantígenos/uso terapéutico , Miastenia Gravis Autoinmune Experimental/tratamiento farmacológico , Linfocitos T , Autoanticuerpos/uso terapéutico , Inmunoglobulina G , Proteínas Tirosina Quinasas/uso terapéutico , MúsculosRESUMEN
Cancerous inhibitor of protein phosphatase 2A (Cip2a) is an oncoprotein, playing important roles in tumor progression. However, the underlying mechanisms by which Cip2a promotes tumor aggressiveness in NSCLC remain to be further investigated. In this study, we found that Cip2a expression is elevated in NSCLC and correlates with poor prognosis. Knockdown of Cip2a significantly reduced the ability of cell proliferation, invasion, and metastasis of NSCLC both in vitro and in vivo. Furthermore, we found that Cip2a promotes tumor progression partly by inducing arginine biosynthesis, and knockdown of Cip2a exhibited a significantly increased sensitivity to arginine deprivation and mTOR inhibition. In addition, we found that p53 mutants in NSCLC cells increased Cip2a expression by inhibiting the activity of wild-type p53. Our findings provide new insights into the mechanisms of Cip2a in promoting tumor progression and suggest that Cip2a represents a potential therapeutic target for treating NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteína p53 Supresora de Tumor , Proliferación Celular/genética , Autoantígenos/genética , Autoantígenos/metabolismo , Autoantígenos/uso terapéutico , Línea Celular TumoralRESUMEN
A 60-year-old man with metastatic renal cell carcinoma presented with a 6-month history of a pruritic, exquisitely painful genital eruption appearing 3 months after initiation of nivolumab. Examination demonstrated a poorly defined, lichenified scrotal plaque studded with erosions, yellow crust, and tense vesicles. There was no other lesion on the body or mucosae. Histopathology revealed a subepidermal blister with a mixed lymphocytic, neutrophilic, and eosinophilic infiltrate. Direct immunofluorescence of perilesional skin demonstrated subclinical blister and linear/fibrillary patchy IgG and IgA along the dermoepidermal junction. Bullous pemphigoid (BP) serologies revealed normal IgG BP230 antibodies and minimally elevated IgG BP180 antibodies. Indirect immunofluorescence revealed positive IgG at the basement membrane ("epidermal pattern") in human split skin and monkey esophagus substrates; no IgA antibodies were detected. The patient was diagnosed with nivolumab-induced localized genital BP (LGBP). BP is a reported adverse effect of immune checkpoint inhibitors including nivolumab; however, cases are typically generalized. LGBP is a rare BP variant typically presenting in children and females; there are few reports of LGBP in adult males. We report a novel case of nivolumab-induced LGBP with unique histopathologic and clinical challenges. LGBP should be considered in patients on immune checkpoint inhibitor therapy with bullous genital eruptions.
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Carcinoma de Células Renales , Neoplasias Renales , Penfigoide Ampolloso , Autoanticuerpos , Autoantígenos/uso terapéutico , Vesícula , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Genitales/patología , Humanos , Inmunoglobulina G/metabolismo , Masculino , Nivolumab/efectos adversosRESUMEN
BACKGROUND & AIMS: Annexin A11 was identified as autoantigen in IgG4-related cholangitis (IRC), a B-cell driven disease. Annexin A11 modulates calcium-dependent exocytosis, a crucial mechanism for insertion of proteins into their target membranes. Human cholangiocytes form an apical 'biliary bicarbonate umbrella' regarded as defense against harmful hydrophobic bile acid influx. The bicarbonate secretory machinery comprises the chloride/bicarbonate exchanger AE2 and the chloride channel ANO1. We aimed to investigate the expression and function of annexin A11 in human cholangiocytes and a potential role of IgG1/IgG4-mediated autoreactivity against annexin A11 in the pathogenesis of IRC. METHODS: Expression of annexin A11 in human liver was studied by immunohistochemistry and immunofluorescence. In human control and ANXA11 knockdown H69 cholangiocytes, intracellular pH, AE2 and ANO1 surface expression, and bile acid influx were examined using ratio microspectrofluorometry, cell surface biotinylation, and 22,23-3H-glycochenodeoxycholic acid permeation, respectively. The localization of annexin A11-mEmerald and ANO1-mCherry was investigated by live-cell microscopy in H69 cholangiocytes after incubation with IRC patient serum containing anti-annexin A11 IgG1/IgG4-autoantibodies or disease control serum. RESULTS: Annexin A11 was strongly expressed in human cholangiocytes, but not hepatocytes. Knockdown of ANXA11 led to reduced plasma membrane expression of ANO1, but not AE2, alkalization of intracellular pH and uncontrolled bile acid influx. High intracellular calcium conditions led to annexin A11 membrane shift and colocalization with ANO1. Incubation with IRC patient serum inhibited annexin A11 membrane shift and reduced ANO1 surface expression. CONCLUSION: Cholangiocellular annexin A11 mediates apical membrane abundance of the chloride channel ANO1, thereby supporting biliary bicarbonate secretion. Insertion is inhibited by IRC patient serum containing anti-annexin A11 IgG1/IgG4-autoantibodies. Anti-annexin A11 autoantibodies may contribute to the pathogenesis of IRC by weakening the 'biliary bicarbonate umbrella'. LAY SUMMARY: We previously identified annexin A11 as a specific autoantigen in immunoglobulin G4-related cholangitis (IRC), a B-cell driven disease affecting the bile ducts. Human cholangiocytes are protected against harmful hydrophobic bile acid influx by a defense mechanism referred to as the 'biliary bicarbonate umbrella'. We found that annexin A11 is required for the formation of a robust bicarbonate umbrella. Binding of patient-derived annexin A11 autoantibodies inhibits annexin A11 function, possibly contributing to bile duct damage by weakening the biliary bicarbonate umbrella in patients with IRC.
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Colangitis/etiología , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Factores Protectores , Anciano , Anexinas/farmacología , Anexinas/uso terapéutico , Autoantígenos/farmacología , Autoantígenos/uso terapéutico , Biopsia/métodos , Biopsia/estadística & datos numéricos , Colangitis/fisiopatología , Femenino , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/fisiopatología , Hígado/patología , Masculino , Persona de Mediana EdadRESUMEN
Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.
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Autoantígenos/uso terapéutico , Autoinmunidad/inmunología , Factores Inmunológicos/uso terapéutico , Regeneración Nerviosa/inmunología , Enfermedades Neurodegenerativas/terapia , Neuroprotección/inmunología , Péptidos/uso terapéutico , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/terapia , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/terapia , Animales , Acetato de Glatiramer/uso terapéutico , Humanos , Inmunización Pasiva , Inmunomodulación , Proteína Básica de Mielina/uso terapéutico , Enfermedades Neurodegenerativas/inmunología , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/terapia , Fragmentos de Péptidos/uso terapéutico , Deficiencias en la Proteostasis , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/terapia , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/terapiaRESUMEN
Lasparaginase enzymes have been a vital component of acute lymphoblastic leukemia therapy for >40 years. Lasparaginase acts by depleting plasma Lasparagine, which is essential to the survival of leukemia cells. In contrast to normal cells, tumor cells cannot synthesize Lasparagine and thus depend on its external uptake for growth. Currently, three bacterial Lasparaginases are used in therapy; however, they are associated with severe sideeffects related to high toxicity and immunogenicity. The introduction of human Lasparaginaselike protein 1 in acute lymphoblastic leukemia treatment would avoid the problems caused by the bacterial enzymes; however, a major difficulty in the therapeutic use of the human enzyme comes from the fact that human Lasparaginase must be activated through an autoprocessing step, which is a lowefficiency process in vitro that results in reduced enzymatic activity. The present review article aimed to contribute to the understanding of the enzyme selfactivation process and focuses on the efforts made for the development of a therapeutic variant of human Lasparaginase.
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Asparaginasa/uso terapéutico , Autoantígenos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Activación Enzimática , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologíaRESUMEN
Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.
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Autoantígenos/administración & dosificación , Autoantígenos/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inmunología , Administración Oral , Animales , Autoantígenos/inmunología , Quimioterapia Adyuvante , Quimioterapia Combinada , Glutamato Descarboxilasa/uso terapéutico , Humanos , Inyecciones Intralinfáticas , Inyecciones Subcutáneas , Insulina/metabolismo , Proinsulina/uso terapéutico , Vitamina D/uso terapéuticoRESUMEN
The trinucleotide repeat containing 6 (TNRC6) family of proteins are core components of RNA interference (RNAi) and consist of three paralogs (TNRC6A, TNRC6B, and TNRC6C). The TNRC6 paralogs associate with argonaute (AGO) protein, the core RNAi factor, and bridge its interactions with other proteins. We obtained TNRC6A and TNRC6B single and double knockout cell lines to investigate how the TNRC6 paralogs contribute to RNAi. We found that TNRC6 proteins are not required for gene silencing when duplex RNAs are fully complementary. TNRC6 expression was necessary for regulation by a microRNA. TNRC6A, but not TNRC6B, expression was necessary for transcriptional activation by a duplex RNA targeting a gene promoter. By contrast, AGO2 is required for all three gene expression pathways. TNRC6A can affect the Dicer localization in cytoplasm versus the nucleus, but none of the three TNRC6 paralogs was necessary for nuclear localization of AGO2. Our data suggest that the roles of the TNRC6 paralogs differ in some details and that TNRC6 is not required for clinical therapeutic silencing mechanisms that involve fully complementary duplex RNAs.
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Proteínas Argonautas/genética , Autoantígenos/genética , Terapia Genética/métodos , Proteínas de Unión al ARN/genética , Proteínas Argonautas/antagonistas & inhibidores , Proteínas Argonautas/uso terapéutico , Autoantígenos/uso terapéutico , Citoplasma/genética , Regulación de la Expresión Génica/genética , Silenciador del Gen , Humanos , MicroARNs/genética , Regiones Promotoras Genéticas/genética , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/uso terapéutico , Repeticiones de Trinucleótidos/genéticaRESUMEN
The exact etiology and pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are still unknown, as a result, available therapeutic options for patients are far from satisfactory. Therefore, there is a need to develop a valid therapeutic approach that can ameliorate the manifestations of CP/CPPS. Fifty male C57BL/6 mice were randomly divided into five groups of ten mice each. All groups except naïve were subcutaneously injected with 0.2 ml of T2 plus complete Freund adjuvant (CFA) on day 0 and 14 to generate valid CP/CPPS model. After successful CP/CPPS induction, model group was injected with 0.2 ml of normal saline while PLGA, PLGA-OVA, and PLGA-T2 groups were administered intravenously with 0.2 ml mixture of PLGA, PLGA-OVA, and PLGA-T2, respectively. Voiding behavior, pain threshold, and hematoxylin and eosin staining were used to assess micturition habits, pain intensity as well as prostate inflammation. Additionally, TNF-α, CRP, and IL-10 levels in plasma were measured by using ELISA kits. Mice administered with PLGA-T2 showed higher pain threshold, lower urine frequencies, mild edema, and inflammation in prostate tissue in comparison to other groups. Moreover, the expression of TNF-α and CRP levels was markedly decreased while IL-10 expression was increased in the PLGA-T2 treatment group as compared to the other groups. Our results showed that nanoparticles conjugated with autoantigen novel peptide T2 could successfully alleviate or even heal CP/CPPS to some extent in mice. This study provides an easy, useful, and economic tool for ameliorating the manifestations of CP/CPPS that will improve the therapeutic approaches.
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Antígenos CD2/uso terapéutico , Nanopartículas/uso terapéutico , Prostatitis/tratamiento farmacológico , Animales , Autoantígenos/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Proteína C-Reactiva/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Modelos Animales de Enfermedad , Interleucina-10/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Electroacupuncture (EA) is widely used in clinical settings to reduce inflammatory pain. Islet-cell autoantigen 69 (ICA69) has been reported to regulate long-lasting hyperalgesia in mice. ICA69 knockout led to reduced protein interacting with C-kinase 1 (PICK1) expression and increased glutamate receptor subunit 2 (GluR2) phosphorylation at Ser880 in spinal dorsal horn. In this study, we evaluated the role of ICA69 in the antihyperalgesic effects of EA and the underlying mechanism through regulation of GluR2 and PICK1 in spinal dorsal horn. Hyperalgesia was induced in mice with subcutaneous plantar injection of complete Freund adjuvant (CFA) to cause inflammatory pain. Electroacupuncture was then applied for 30 minutes every other day after CFA injection. When compared with CFA group, paw withdrawal frequency of CFA+EA group was significantly decreased. Remarkable increases in Ica1 mRNA expression and ICA69 protein levels on the ipsilateral side were detected in the CFA+EA group. ICA69 expression reached the peak value around day 3. More importantly, ICA69 deletion impaired the antihyperalgesic effects of EA on GluR2-p, but PICK1 deletion could not. Injecting ICA69 peptide into the intrathecal space of ICA69-knockout mice mimicked the effects of EA analgesic and inhibited GluR2-p. Electroacupuncture had no effects on the total protein of PICK1 and GluR2. And, EA could increase the formation of ICA69-PICK1 complexes and decrease the amount of PICK1-GluR2 complexes. Our findings indicate that ICA69 mediates the antihyperalgesic effects of EA on CFA-induced inflammatory pain by regulating spinal GluR2 through PICK1 in mice.
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Autoantígenos/metabolismo , Proteínas Portadoras/metabolismo , Electroacupuntura/métodos , Regulación de la Expresión Génica/genética , Proteínas Nucleares/metabolismo , Receptores AMPA/metabolismo , Médula Espinal/metabolismo , Animales , Autoantígenos/química , Autoantígenos/genética , Autoantígenos/uso terapéutico , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Modelos Animales de Enfermedad , Adyuvante de Freund/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Inmunoprecipitación , Inflamación/inducido químicamente , Inflamación/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Nucleares/genética , Dolor/complicaciones , Dolor/etiología , Manejo del Dolor , Fosforilación/fisiología , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
Contemporary approaches to treating autoimmune diseases like multiple sclerosis broadly modulate the immune system and leave patients susceptible to severe adverse effects. Antigen-specific immunotherapies (ASIT) offer a unique opportunity to selectively suppress autoreactive cell populations but have suffered from marginal efficacy even when employing traditional adjuvants to improve delivery. The development of immunologically active antigen delivery vehicles could potentially increase the clinical success of antigen-specific immunotherapies. An emulsion of the antioxidant tocopherol delivering an epitope of proteolipid protein autoantigen (PLP139-151) yielded significant efficacy in mice with experimental autoimmune encephalomyelitis (EAE). In vitro studies indicated tocopherol emulsions reduced oxidative stress in antigen-presenting cells. Ex vivo analysis revealed that tocopherol emulsions shifted cytokine responses in EAE splenocytes. In addition, IgG responses against PLP139-151 were increased in mice treated with tocopherol emulsions delivering the antigen, suggesting a possible skew in immunity. Overall, tocopherol emulsions provide a functional delivery vehicle for ASIT capable of ameliorating autoimmunity in a murine model.
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Autoantígenos/uso terapéutico , Emulsiones/química , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Tocoferoles/química , Tocoferoles/uso terapéutico , Animales , Autoantígenos/administración & dosificación , Citocinas/metabolismo , Femenino , Tolerancia Inmunológica/efectos de los fármacos , Inmunoterapia/métodos , Ratones , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Bazo/citologíaRESUMEN
Introducción: las fisuras anales son un problema de salud importante en la población cubana, incluso con la supresión de los factores desencadenantes, muchas de ellas tienden a la cronicidad; su evolución es tórpida, y es elevado el riesgo de complicación de las mismas. Objetivo: evaluar la cicatrización de las fisuras anales mediante lisado plaquetario en el Hospital General Docente Comandante Pinares de San Cristóbal. Método: se realizó un estudio cuasi experimental en el servicio de cirugía general del Hospital General Docente Comandante Pinares desde enero 2015 hasta junio 2017. Se incluyeron en el estudio todos los pacientes adultos, de ambos sexos, atendidos por el diagnóstico de fisura anal con inadecuada respuesta al tratamiento convencional y sin otras enfermedades de base que impidieran el uso de la terapia regenerativa. A todos los pacientes se les solicitó el consentimiento informado previa explicación de las características del estudio. Resultados: la hemorroidectomía fue el proceder más frecuente asociado a las fisuras anales. El dolor fue el síntoma predominante antes del tratamiento. La reducción del área de la fisura fue evidente en los tratados con lisado. El efecto final en los pacientes tratados con el método fue positivo. Conclusiones: se comprobó que el lisado plaquetario usado para la cicatrización de la fisura anal crónica fue efectivo con un resultado de satisfacción por parte de los pacientes, con un mínimo de reacciones adversas. Puede representar un futuro promisorio en el tratamiento de esta enfermedad(AU)
Introduction: Anal fissures are an important health problem in the Cuban population, even with the suppression of the triggering factors, many of them tend to chronicity; its evolution is torpid, and their risk for complication is high. Objective: To evaluate the healing of anal fissures by platelet lysate in Comandante Pinares General Teaching Hospital in San Cristóbal. Method: A quasi-experimental study was performed in the general surgery service of Comandante Pinares General Teaching Hospital, from January 2015 to June 2017. All adult patients, of both sexes, were attended upon diagnosis of anal fissure and were included in the study. with inadequate response to conventional treatment and without other underlying diseases that could prevent the use of regenerative therapy. All patients were asked for their informed consent prior explanation of the study characteristics. Results: Hemorrhoidectomy was the most frequent procedure associated with anal fissures. Pain was the predominant symptom before treatment. The reduction in the area of ââthe fissure was evident in those patients treated with the lysate. The final effect in patients treated with the method was positive. Conclusions: The usage of the platelet lysate for the healing of chronic anal fissure proved effective, with a result of patient satisfaction, with a minimum of adverse reactions. It may represent a promising future in the treatment of this disease(AU)
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Humanos , Masculino , Femenino , Autoantígenos/uso terapéutico , Factores Desencadenantes , Medicina Regenerativa/métodos , Fisura Anal/diagnóstico , Recolección de Datos/estadística & datos numéricosRESUMEN
Background: Autologous whole blood (AWB) administration is described as alternative/complementary medical practice widely employed in medical and veterinary therapy against infections, chronic pathologies and neoplasias. Our aim is to investigate in vivo biological effect of AWB using healthy murine models under the course of Trypanosoma cruzi acute infection. Methods: The first set of studies consisted of injecting different volumes of AWB and saline (SAL) into the posterior region of quadriceps muscle of healthy male Swiss mice under distinct therapeutic schemes evaluating: animal behavior, body and organ weight, hemogram, plasmatic biochemical markers for tissue damage and inflammatory cytokine levels and profile. To assess the impact on the experimental T. cruzi infection, different schemes (prior and post infection) and periods of AWB administration (from one up to 10 days) were conducted, also employing heterologous whole blood (HWB) and evaluating plasma cytokine profile. Results: No major adverse events were observed in healthy AWB-treated mice, except gait impairment in animals that received three doses of 20 L AWB in the same hind limb. AWB and SAL triggered an immediate polymorphonuclear response followed by mononuclear infiltrate. Although SAL triggered an inflammatory response, the kinetics and intensity of the histological profile and humoral mediator levels were different from AWB, the latter occurring earlier and more intensely with concomitant elevation of plasma IL-6. Inflammatory peak response of SAL, mainly composed of mononuclear cells with IL-10, was increased at 24 h. According to the mouse model of acute T. cruzi infection, only minor decreases ( 30%) in the parasitemia levels were produced by AWB and HWB given before and after infection, without protecting against mortality. Rises in IFN-gamma, TNF-alpha and...
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Animales , Ratones , Autoantígenos/uso terapéutico , Transfusión de Sangre Autóloga , Trypanosoma cruziRESUMEN
Studies with immunologics have shown that the natural history of Type 1 diabetes can be modified. These studies have targeted key mediators of the disease and recent analyses, together with studies in preclinical models have identified mechanisms that may be involved in the clinical effects. Several issues remain including specificity of the interventions, adverse effects of the treatments, and duration of their effects. Future studies are likely to include more specific approaches with agents such as cell therapies with selected immune regulatory subsets, antigen specific therapies, and combinations of agents with complementary mechanisms of activity.
Asunto(s)
Autoantígenos/uso terapéutico , Productos Biológicos/uso terapéutico , Diabetes Mellitus Tipo 1/terapia , Inmunoterapia/métodos , Células Secretoras de Insulina/patología , Animales , Autoantígenos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Modelos Animales de Enfermedad , Humanos , Tolerancia Inmunológica , Células Secretoras de Insulina/efectos de los fármacos , Terapia Molecular DirigidaRESUMEN
Citrullinated peptides are used for measuring anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). Accumulation of citrullinated proteins in the inflamed synovium suggests that they may be good targets for inducing peripheral tolerance. In view of the multiplicity of citrullinated autoantigens described as ACPA targets, we generated a multiepitope citrullinated peptide (Cit-ME) from the sequences of major citrullinated autoantigens: filaggrin, ß-fibrinogen, vimentin, and collagen type II. We assessed the ability of Cit-ME or the citrullinated ß60-74 fibrinogen peptide (ß60-74-Fib-Cit) which bears immunodominant citrullinated epitopes (i) to modify cytokine gene expression and (ii) to modulate Treg and Th17 subsets in PBMC derived from newly diagnosed untreated RA patients. RA patient's PBMC incubated with Cit-ME or ß60-74-Fib-Cit, showed upregulation of TGF-ß expression (16% and 8%, resp.), and increased CD4+Foxp3+ Treg (22% and 19%, resp.). Both peptides were shown to downregulate the TNF-α and IL-1ß expression; in addition, Cit-ME reduced CD3+IL17+ T cells. We showed that citrullinated peptides can modulate the expression of anti- and proinflammatory cytokines in PBMC from RA patients as well as the proportions of Treg and Th17 cells. These results indicate that citrullinated peptides could be active in vivo and therefore might be used as immunoregulatory agents in RA patients.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Autoantígenos/inmunología , Autoantígenos/uso terapéutico , Adulto , Anciano , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Autoantígenos/química , Citrulinación , Colágeno Tipo II/metabolismo , Epítopos , Femenino , Fibrinógeno/metabolismo , Proteínas Filagrina , Humanos , Inmunomodulación/fisiología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Vimentina/metabolismo , Adulto JovenRESUMEN
AIM: Based on the ability of apoptosis to induce immunological tolerance, liposomes were generated mimicking apoptotic cells, and they arrest autoimmunity in Type 1 diabetes. Our aim was to validate the immunotherapy in other autoimmune disease: multiple sclerosis. MATERIALS & METHODS: Phosphatidylserine-rich liposomes were loaded with disease-specific autoantigen. Therapeutic capability of liposomes was assessed in vitro and in vivo. RESULTS: Liposomes induced a tolerogenic phenotype in dendritic cells, and arrested autoimmunity, thus decreasing the incidence, delaying the onset and reducing the severity of experimental disease, correlating with an increase in a probably regulatory CD25+ FoxP3- CD4+ T-cell subset. CONCLUSION: This is the first work that confirms phosphatidylserine-liposomes as a powerful tool to arrest multiple sclerosis, demonstrating its relevance for clinical application.
Asunto(s)
Autoantígenos/administración & dosificación , Inmunoterapia/métodos , Liposomas/química , Esclerosis Múltiple/terapia , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Péptidos/administración & dosificación , Fosfatidilserinas/química , Animales , Autoantígenos/inmunología , Autoantígenos/uso terapéutico , Femenino , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Glicoproteína Mielina-Oligodendrócito/uso terapéutico , Péptidos/inmunología , Péptidos/uso terapéutico , Linfocitos T Reguladores/inmunologíaRESUMEN
Autoimmune diseases occur when the immune system incorrectly recognizes self-molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLRs), pathways usually involved in generating immune responses against pathogens, play a significant role in driving autoimmune disease in both humans and animal models. We reasoned polyplexes formed from myelin self-antigen and regulatory TLR antagonists might limit TLR signaling during differentiation of myelin-specific T cells, inducing tolerance by biasing T cells away from inflammatory phenotypes. Complexes were formed by modifying myelin peptide with cationic amino acids to create peptides able to condense the anionic nucleic-acid based TLR antagonist. These immunological polyplexes eliminate synthetic polymers commonly used to condense polyplexes and do not rely on gene expression; however, the complexes mimic key features of traditional polyplexes such as tunable loading and co-delivery. Using these materials and classic polyplex analysis techniques, we demonstrate condensation of both immune signals, protection from enzymatic degradation, and tunable physicochemical properties. We show polyplexes reduce TLR signaling, and in primary dendritic cell and T cell co-culture, reduce myelin-driven inflammation. During mouse models of MS, these tolerogenic polyplexes improve the progression, severity, and incidence of disease.