IL-21 induces IL-22 production in CD4+ T-cells

IL-22 produced by innate lymphoid cells (ILCs) and CD4+ T cells plays an important role in host defense and mucosal homeostasis, thus it is important to investigate the mechanisms that regulate IL-22 production. We investigated the regulation IL-22 production by CD4+ T cells. Here we show that IL-21 triggers IL-22, but not IL-17 production by CD4+ T cells. STAT3, activated by IL-21, controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR). Moreover, IL-21 and AhR signaling in T cells control IL-22 production and the development of dextran sodium sulfate-induced colitis in ILC-deficient mice. Thus, we have identified IL-21 as an inducer of IL-22 production in CD4+ T cells in vitro and in vivo

Antitumor responses stimulated by dendritic cells are improved by triiodothyronine binding to the thyroid hormone receptor β

Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) β mutant mouse (TRβPV) to establish the relevance of the T3-TRβ system in vivo. In this model, TRβ signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRβ increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNγ-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TRβ signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy.Fil: Alamino, Vanina Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Mascanfroni, Ivan Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Montesinos, Maria del Mar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Gigena, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Donadio, Ana Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Milotich, Sonia I.. Hospital Materno-Neonatal Ramon Carrillo; ArgentinaFil: Cheng, Sheue Yann. National Institutes Of Health. National Cancer Institute; Estados UnidosFil: Masini Repiso, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Pellizas, Claudia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentin

Galectin-1 Deactivates Classically Activated Microglia and Protects from Inflammation-Induced Neurodegeneration

SummaryInflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS

Proteínas totales y perfiles SDS-PAGE de suelos agrícolas bajo fertilización mineral

Los microorganismos son fundamentales para el mantenimiento de las funciones de suelos naturales y agrícolas. La identificación de proteínas del suelo podría proporcionar una valiosa información sobre las capacidades funcionales de los microorganismos que lo habitan y que están sujetos a diferentes condiciones de estrés. El estudio de las proteínas del suelo podría ser utilizado para caracterizar la respuesta de las comunidades microbianas a la aplicación de contaminantes, fertilizantes u otros cambios ambientales. El objetivo del presente trabajo fue determinar el impacto de diferentes combinaciones de fertilizantes minerales en los perfiles proteínicos de un suelo agrícola propio de la región con mayor productividad del país. Los muestreos realizados en el presente estudio estuvieron bajo un sistema conservacionista de rotación de cultivos (maíz/soja) y siembra directa por más de 10 años. Se midió el contenido de proteínas totales y se realizaron perfiles proteicos SDS-PAGE. Se observaron, incrementos en el contenido de proteínas totales en los suelos fertilizados en relación al testigo. La aplicación de N alteró el perfil de bandas proteicas encontrado por SDS-PAGE, solo en los suelos con cultivo de superficie maíz.The microorganisms are fundamental for the maintenance of the functions of natural and agricultural soils. In this sense, the identification of soil proteins could provide valuable information about the functional capacities of the microorganisms that inhabit it and that are subject to different stress conditions. The study of soil proteins could be used to characterize the response of microbial communities to anthropic disturbances as the application of contaminants, fertilizers or other environmental changes. The aim of this work was to determine the impact of different combinations of mineral fertilizers on the protein profiles of an agricultural land typical of the region with the highest productivity in the country. The samplings carried out in the present study were under a conservationist system of crop rotation (corn / soybean) and no till for more than 10 years. The total protein content was measured and SDS-PAGE protein profiles were made. Increases in the total protein content in the fertilized soils were observed in relation to the control. The application of N altered the profile of protein bands found by SDS-PAGE, only in soils with corn.Instituto de Patología VegetalFil: Verdenelli, Romina Aylen. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Ciencias y Tecnología de los Alimentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Mascanfroni, Gisela Daniela. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Ciencias y Tecnología de los Alimentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Dominchin, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Ciencias y Tecnología de los Alimentos; ArgentinaFil: Barbero, Florencia Magali. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Ciencia y Tecnología de los Alimentos; ArgentinaFil: Vargas Gil, Silvina. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Patología Vegetal; ArgentinaFil: Meriles, Jose Manuel. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Ciencias y Tecnología de los Alimentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; Argentin

A glycosylation-dependent pathway of non-canonical VEGFR2 activation links tumor hypoxia to vascular remodeling and immunity.

The mechanisms linking tumor hypoxia, neovascularization and immunity are poorlyunderstood. Resistance to VEGF-targeted antiangiogenic therapies suggests thecontribution of non-canonical pathways to hypoxia-driven neovascularization. Wepreviously demonstrated an essential role of galectin-1 (Gal-1) in the control of tumorgrowth by favoring tumor-immune escape. The present study was conducted to elucidatewhether Gal1-glycan lattices link tumor hypoxia to neovascularization and to investigatewhether disruption of these lattices using an anti Gal1 mAb, may contribute to remodelingtumor vascular networks and stimulation of anti-tumor immune responses. For thispurpose, we first examined the ?glycosylation signature? of endothelilal cells (ECs) in restingconditions or exposed to proliferative, tolerogenic, inflammatory or hypoxic stimuli. Incontrast to ECs stimulated with pro-inflammatory stimuli, ECs exposed to tolerogenic,proliferative or hypoxic microenvironment exhibited a substantial up-regulation of therepertoire of cell surface glycans that are critical for Gal-1 binding and angiogenesis(p<0.01). Screening of the phosphorylation status of a spectrum of growth factor receptorsrevealed a 2-fold increase in phosphorylation of VEGFR2, Akt and Erk1/2 upon exposureto Gal1, a pattern comparable to that induced by VEGF. In this regard, pharmacologicalinhibition of Akt or Erk1/2 or interruption of GnTV-mediated N-glycan branching (but notGCNT1-mediated core 2-O-glycan elongation) prevented Gal1 signaling and abrogatedECs proliferation (p<0.01), migration (p<0.01) and angiogenesis (p<0.05). Co-Ipexperiments revealed specific association of Gal1 with VEGFR2 through N-glycandependentinteractions. Consistently, VEGFR2 blockade prevented Gal1-induced ECsmigration (p<0.01) and morphogenesis (p<0.05), whereas blockade of VEGFR1, VEGFR3,or VEGF had no effect, suggesting that signaling established between lectins and glycansmight serve as alternative pathways by mimicking ?cognate ligands?, thus preserving criticalprocesses such as angiogenesis. Furthermore, hypoxia promoted ROS/NF-B-dependentHIF-1-independent up-regulation of tumor Gal1 (p<0.01). mAb- or shRNA-mediateddisruption of Gal1-glycan lattices attenuated hypoxia-driven angiogenesis, while promotingpericyte maturation and vascular remodeling as shown by increased association of ECswith mature pericytes (SMA+, desmin+ and RGS5-) (2-fold; p<0.01), decreased vesseldiameter (2.7 fold; p<0.01) and alleviation of hypoxia in tumors treated with anti-Gal1 mAb.Moreover, anti-Gal-1 mAb-treated tumors showed a significant reduction in tumor growth(p<0.01) and evoked a T-cell specific immune response, as shown by increased T-cellproliferation (p<0.01) and augmented IFN- (p<0.05) and IL-17 (p<0.05) productioncompared to mice receiving control isotype. Moreover, tumor draining LN of mAb-treatedmice had lower frequency of regulatory T cells (p<0.05) and lower IL-10 secretion (p<0.05)compared to mice receiving isotype control. Hence, disruption of lectin-glycan lattices, notonly evokes an unleashed anti tumor immune response, but also reduces angiogenesisand favors remodeling of tumor vascular networks, highlighting the versatility ofendogenous lectins and the dynamics of the ?glycome? during cancer progression.Fil: Croci Russo, Diego Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Salatino, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ouyang, J.. Dana Farber Cancer Institute;Fil: Rubinstein, N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Mascanfroni, Ivan Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Cerliani, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ilarregui, Juan Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sundblad, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Toscano, Marta Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Domaica, Carolina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Dergan Dylon, Leonardo Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Croci, M. C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Albini, A.. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; ItaliaFil: Shipp, M. A.. Dana Farber Cancer Institute;Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaKeystone simposia on molecular and celullar biology: new frontiers at the interface of immunity and glycobiologyLake LouisCanadákeystonesymposi

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

Inflammatory bowel disease (IBD) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD. However, the mechanisms through which purine metabolism modulates IBD remain to be established. Here, we found that mucosal expression of genes involved in the purine metabolic pathway is altered in patients with active ulcerative colitis (UC), which is associated with elevated gene expression signatures of the group 3 innate lymphoid cell (ILC3)–interleukin (IL)‐22 pathway. In mice, blockade of ectonucleotidases (NTPDases), critical enzymes for purine metabolism by hydrolysis of extracellular adenosine 5′‐triphosphate (eATP) into adenosine, exacerbates dextran‐sulfate sodium‐induced intestinal injury. This exacerbation of colitis is associated with reduction of colonic IL‐22‐producing ILC3s, which afford essential protection against intestinal inflammation, and is rescued by exogenous IL‐22. Mechanistically, activation of ILC3s for IL‐22 production is reciprocally mediated by eATP and adenosine. These findings reveal that the NTPDase‐mediated balance between eATP and adenosine regulates ILC3 cell function to provide protection against intestinal injury and suggest potential therapeutic strategies for treating IBD by targeting the purine–ILC3 axis

Glicômica da resposta imune: o universo de glicanos e lectinas em microambientes inflamatórios e neoplásicos

Las galectinas, una familia de lectinas que reconocen glico-conjugados específicos en la superficie celular y la matriz, participan en diversos procesos biológicos como reguladores de la ho-meostasis de la respuesta inmune y de la progresión tumoral. Considerando el papel inmunomodulador de Galectina-1 (Gal-1) en modelos de inflamación crónica y su contribución a la creación de microambientes tolerogénicos, durante los últimos años exploramos el impacto de esta proteína sobre el balance de células T y la funcionalidad de células dendríticas (CDs). Mientras las células Th1 y Th17 poseen el repertorio de glicanos necesarios para la unión de Gal-1, los linfocitos Th2 son resistentes a la unión de esta proteína, lo cual explicaría el incremento en la susceptibilidad de los linfocitos Th1 y Th17 a la apoptosis inducida por Gal-1 y la consecuente desviación en el balance de la respuesta inmune hacia un perfil Th2. Además, identificamos un circuito tolerogénico en el que Gal‐1 induce la diferenciación de CDs tolerogénicas productoras de IL‐27, la consecuente expansión de células T regulatorias productoras de IL‐10 y la supresión de la inflamación mediada por células Th1 y Th17. Postulamos un nuevo mecanismo de regulación homeostática de la respuesta inmune basado en la interacción entre Gal‐1 y sus gli-canos específicos, el cual permite anticipar nuevos horizontes terapéuticos, en los que la modulación de la expresión de Gal‐1 o sus glicanos nos permitiría regular la respuesta inmune.Galectins, a family of endogenous glycan-binding proteins able to recognize specific glycoconjugates on cell surface and extracellular matrix, control critical immunological processes involved in immune homeostasis and tumor progression. Given the immunosuppressive role of Galectin-1 (Gal-1) in different models of chronic inflammation and its contribution to the creation of tolerogenic microenvironments in cancer and pregnancy models, the impact of this protein on T helper cell balance and dendritic cells (DCs) functionality was explored. A novel mechanism, based on the differential glycosylation of T helper cell subsets, by which Gal-1 preferentially eliminates antigen-specific Th1 and Th17 cells, leading to a shift toward a Th2 profile was identified. While Th1- and Th-17-differentiated cells expressed the repertoire of cell surface glycans that are critical for Gal-1-induced cell death, Th2 cells are protected from Gal-1 through differential sialylation of cell surface glycoproteins. More recently, the ability of Gal-1 to trigger the differentiation of tolerogenic dendritic cells (DCs), which promote resolution of autoimmune inflammation, was demonstrated. A tolerogenic circuit linking Gal-1 signaling, IL-27-producing DCs and IL-10-secreting T cells was identified. It can be postulated that molecular interactions between endogenous galectins and specific glycans constitute a novel mechanism of homeostatic regulation of immune responses. Understanding the role of protein-glycan interactions in the establishment of tolerogenic or inflammatory programs will enable the design of more rational immunotherapeutic strategies with broad biomedical implications.As galectinas, uma família de lectinas que reconhecem gli-coconjugados específicos na superfície celular e a matriz, participam em diversos processos biológicos como reguladores da homeostase da resposta imune e da progressão tu-moral. Considerando o papel imunomodulador de Galec-tina-1 (Gal-1) em modelos de inflamação crônica e sua contribuição à criação de microambientes tolerogênicos, durante os últimos anos exploramos o impacto desta proteína sobre o balanço de células T e a funcionalidade de células dendríticas (CDs). Enquanto as células Th1 e Th17 possuem o repertório de glicanos necessários para a união de Gal-1, os linfócitos Th2 são resistentes à união desta proteína, o qual explicaria o incremento na suscetibilidade dos linfóci-tos Th1 e Th17 à apoptose induzida por Gal-1 e o conse-guinte desvio no balanço da resposta imune para um perfil Th2. Além disso, identificamos um circuito tolerogênico no qual Gal‐1 induz a diferenciação de CDs tolerogênicas pro-dutoras de IL‐27, a conseguinte expansão de células T re-gulatórias produtoras de IL‐10 e a supressão da inflamação mediada por células Th1 e Th17. Postulamos um novo mecanismo de regulação homeostática da resposta imune ba-seado na interação entre Gal‐1 e seus glicanos específicos, que permite antecipar novos horizontes terapêuticos, nos quais a modulação da expressão de Gal‐1 ou seus glicanos nos permitiria regular a resposta imune.Fil: Sundblad, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Cerliani, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Compagno, Daniel Georges. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Croci Russo, Diego Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: D'alotto Moreno, Tomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Dergan Dylon, Leonardo Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Di Lella, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Gatto, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Gentilini, Lucas Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Giribaldi, María Laura. Universidad de Buenos Aires. Facultad de Cs.exactas y Naturales. Departamento de Quimica Biologica. Laboratorio de Analisis Biologicos E Inmunoquimica; ArgentinaFil: Guardia, Carlos Manuel Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Ilarregui, Juan Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Laderach, Diego Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Martínez Allo, Verónica Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Mascanfroni, Ivan Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Mendez Huergo, Santiago Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Salatino, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Stupirski, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Toscano, Marta Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentin

Graves' disease is associated with a defective expression of the immune regulatory molecule galectin-9 in antigen-presenting dendritic cells

Introduction Patients with autoimmune thyroid disease (AITD) show defects in their immune-regulatory mechanisms. Herein we assessed the expression and function of galectin-1 and galectin-9 (Gal-1, Gal-9) in dendritic cells (DCs) from patients with AITD. Materials and Methods Peripheral blood samples from 25 patients with Graves’ disease (GD), 11 Hashimoto’s thyroiditis (HT), and 24 healthy subjects were studied. Thyroid tissue samples from 44 patients with AITD and 22 patients with goiter were also analyzed. Expression and function of Gal-1 and Gal-9 was assessed by quantitative RT-PCR, immunofluorescence and flow cytometry. Results A diminished expression of Gal-9, but not of Gal-1, by peripheral blood DCs was observed in GD patients, mainly in those with Graves´ ophthalmopathy, and a significant negative association between disease severity and Gal-9 expression was detected. In addition, the mRNA levels of Gal-9 and its ligand TIM-3 were increased in thyroid tissue from AITD patients and its expression was associated with the levels of Th1/Th12/Th17 cytokines. Immunofluorescence studies proved that intrathyroidal Gal-9 expression was confined to DCs and macrophages. Finally, in vitro functional assays showed that exogenous Gal-9 had a suppressive effect on the release of Th1/Th2/Th17 cytokines by DC/lymphocyte autologous co-cultures from both AITD patients and healthy controls. Conclusions The altered pattern of expression of Gal-9 in peripheral blood DCs from GD patients, its correlation with disease severity as well as its ability to suppress cytokine release suggest that Gal-9 could be involved in the pathogenesis of AITDThis work was supported by grants from the Fondo de Investigaciones Sanitarias (FISS) PI10/ 02521 and S2010/BMD-2328 TIRONET (Comunidad de Madrid), Spain (to MM) and the Fondo de Cooperación Internacional en Ciencia y Tecnología (FONCICYT) 95395, European Union-México (to RGA

Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity

© The American Society of Gene and Cell Therapy. Treatment of chronic neurodegenerative diseases such as multiple sclerosis (MS) remains a major challenge. Here we genetically engineer neural stem cells (NSCs) to produce a triply therapeutic cocktail comprising IL-10, NT-3, and LINGO-1-Fc, thus simultaneously targeting all mechanisms underlie chronicity of MS in the central nervous system (CNS): persistent inflammation, loss of trophic support for oligodendrocytes and neurons, and accumulation of neuroregeneration inhibitors. After transplantation, NSCs migrated into the CNS inflamed foci and delivered these therapeutic molecules in situ. NSCs transduced with one, two, or none of these molecules had no or limited effect when injected at the chronic stage of experimental autoimmune encephalomyelitis; cocktail-producing NSCs, in contrast, mediated the most effective recovery through inducing M2 macrophages/microglia, reducing astrogliosis, and promoting axonal integrity and endogenous oligodendrocyte/neuron differentiation. These engineered NSCs simultaneously target major mechanisms underlying chronicity of multiple sclerosis (MS) and encephalomyelitis (EAE), thus representing a novel and potentially effective therapy for the chronic stage of MS, for which there is currently no treatment available