23 research outputs found
Role of fucosyltransferase-VII and P-selectin glycoprotein ligand-1 in the migration of CD4+CD25+ regulatory T cells in inflamed brain
No full textROLE OF FUCOSYLTRANSFERASE-VII AND P-SELECTIN GLYCOPROTEIN LIGAND-1 IN THE MIGRATION OF CD4+CD25+ REGULATORY CELLS IN INFLAMED BRAIN
No full textCD4+CD25+ regulatory T (Treg) cells participate in immunologic homeostasis by active suppression of inappropriate immune responses and are able to inhibit a variety of autoimmune and inflammatory diseases. Treg cells inhibit the activation of autoreactive T cells and suppress organ-specific autoimmunity. The mechanisms of Treg cells involved in the regulation of experimental autoimmune encephalomyelitis (EAE) are not well understood. Recent studies have shown a direct involvment of Treg cells in the natural resolution of EAE within the central nervous system (CNS) and a strong correlation between their migration pattern and their ability to control inflammatory responses. However, the molecular mechanisms controlling the migration of Tregs in inflamed brain are not known. P-selectin glycoprotein ligand-1 (PSGL-1) and alpha (1,3) fucosyltransferases (FucT), enzymes that catalyze the glycosylation of PSGL-1 and control its functionality, are molecules involved in the migration of leukocytes in sites of inflammation. The GOAL of this study was to determine the role of PSGL-1 in the migration of Treg cells in mice with EAE.
METHODS: Active and transfer EAE were performed in WT/C57Bl/6, FucT-VII and PSGL-1 deficient (FucT-VII-/- and PSGL-1-/-) mice using MOG35-55 peptide. CD4+CD25+ cells were obtained by magnetic cell sorting. Flow cytometry and ImageStream technology were used to determine the expression and distribution of adhesion molecules and binding capacity to P-selectin and E-selectin chimeras. Migration properties of WT, FucT-VII-/- and PSGL-1-/- Tregs were determined with in vivo migration assays using 3H-glycerol-labeled Tregs. Intravital microscopy experiments were performed in order to determine the ability of WT, FucT-VII-/- and PSGL-1-/- Tregs to interact with inflamed brain endothelium.
RESULTS: Encephalitogenic T cells produced from FucT-VII-/- and PSGL-1-/- mice transferred a significantly more severe disease that WT T cells. We observed no significant differences in the expression of adhesion molecules and IL-4 and IFN-γ production of autoreactive T cells from PSGL-1 and FucT-VII deficient mice. However, co-cultures with CD4+CD25+ Tregs and effector cells showed that deficiency of PSGL-1 and FucT-VII leads to a marked decrease of suppression capacity of Tregs. Interestingly, activated CD4+CD25+ Tregs have increased expression of functional PSGL-1 and a significantly higher suppressor activity in vitro when compared to naïve cells. In addition, activated Tregs display increased migration capacity in inflamed brain in mice with EAE. Both activated and naïve WT Treg cells preferentially migrated into the CNS in the pre-clinical phase of active EAE, than at disease onset. Treg cells from FucT-VII-/- and PSGL-1-/- mice present decreased migration ability to inflamed CNS when compared to WT Tregs. Moreover, intravital microscopy experiments showed a dramatic decrease of adhesive interactions in inflamed brain microcirculation in FucT-VII-/- and PSGL-1-/- Tregs. Finally, Tregs deficient of PSGL-1 and FucT-VII displayed a reduced capacity to suppress active EAE when compared to WT cells.
CONCLUSION: Our data demonstrate that PSGL-1 and the fucosylation of its glycans by FucT-VII are involved in the suppression mediated by CD4+CD25+ Treg cells in MOG-induced EAE. Moreover, in addition to a role in cell-cell contact required for efficient suppression, our results suggest a key role of PSGL-1 and FucT-VII activity in the recruitment of CD4+CD25+ cells into the brain of mice with EAE
Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism
No full textIt is well known that the cannabinoid system has a significant role in the regulation of the immune responses. Cannabinoid receptors CB1 and CB2 are expressed on T lymphocytes and mediate the immunomodulatory effects of cannabinoids on T cell functions. Here we show that the treatment of proteolipid protein (PLP)139-151-specific T cells with SR141716A, a CB1 inverse agonist and prototype of the diarylpyrazoles series, induced a strong inhibition of firm adhesion in inflamed brain venules in intravital microscopy experiments. In contrast, SR144528, a potent CB2 inverse agonist, had no significant effect on both rolling and arrest of activated T cells. In addition, two analogs of SR141716A and CB1 inverse agonists, AM251 and AM281 inhibited encephalitogenic T cell adhesion suggesting that selective CB1 inverse agonism interfere with lymphocyte trafficking in the CNS. Flow cytometry experiments showed that CB1 inverse agonists have no effect on adhesion molecule expression suggesting that CB1 blockade interferes with signal transduction pathways controlling T cell adhesion in inflamed brain venules. In addition, integrin clustering was not altered after treatment with CB1 inverse agonists suggesting that adhesion blockade is not due to the modulation of integrin valency. Notably, the inhibitory effect exerted by AM251 and AM281 on the adhesive interactions was completely reverted in the presence of protein kinase A (PKA) inhibitor H89, suggesting that cAMP and PKA activation play a key role in the adhesion blockade mediated by CB1 inverse agonists. To further strengthen these results and unveil a previously unknown inhibitory role of cAMP on activated T cell adhesion in vivo in the context of CNS inflammation, we showed that intracellular increase of cAMP induced by treatment with Bt2cAMP, a permeable analog of cAMP, and phosphodiesterase (PDE) inhibitor theophylline efficiently blocked the arrest of encephalitogenic T cells in inflamed brain venules. Our data show that modulation of CB1 function has anti-inflammatory effects and suggests that inverse agonism of CB1 block signal transduction mechanisms controlling encephalitogenic T cells adhesion in inflamed brain venules by a PKA-dependent mechanism
Preventive and therapeutic beneficial effect of adipose-derived mesenchymal stem cells in chronic EAE
No full text
CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1.
No full textultiple sclerosis (MS) is considered an autoimmune inflammatory disease of the central nervous system. Under physiologic conditions, we compared the adhesiveness of CD4+ and CD8+ lymphocytes from nontreated patients with acute, relapsing-remitting multiple sclerosis (RRMS) and from healthy donors. We show that in patients with RRMS CD8+, but not with RRMS CD4+, T cells display increased rolling and arrest in inflamed murine brain venules. Moreover, CD8+, but not CD4+, lymphocytes from MS patients show increased rolling on P-selectin in vitro. Anti-P-selectin glycoprotein ligand-1 (PSGL-1) antibodies dramatically block the recruitment of CD8+ cells in brain vessels of patients with MS, suggesting that PSGL-1 represents a novel pharmaceutical target that may be exploited to block the selective entrance of CD8+ cells during early inflammation. Vascular cell adhesion molecule-1 (VCAM-1), but not PSGL-1, is critical for the adhesion of CD4+ cells in MS patients, highlighting a fundamental dichotomy in the mechanisms governing the recruitment of lymphocyte subsets in RRMS. Importantly, 7-color fluorescence-activated cell sorter (FACS) analysis, together with functional data, indicates that a large fraction of CD8+ cells from MS patients display the characteristics of memory-effector phenotype. In conclusion, our results show that CD8+, but not CD4+, T cells from patients with RRMS in the acute phase of the disease display increased ability to be recruited in inflamed brain venules
Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis
No full textMesenchymal stem cells (MSCs) represent a promising therapeutic approach for neurological autoimmune diseases; previous studies have shown that treatment with bone marrow-derived MSCs induces immune modulation and reduces disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we show that intravenous administration of adipose-derived MSCs (ASCs) before disease onset significantly reduces the severity of EAE by immune modulation and decreases spinal cord inflammation and demyelination. ASCs preferentially home into lymphoid organs but also migrates inside the central nervous system (CNS). Most importantly, administration of ASCs in chronic established EAE significantly ameliorates the disease course and reduces both demyelination and axonal loss, and induces a Th2-type cytokine shift in T cells. Interestingly, a relevant subset of ASCs expresses activated alpha 4 integrins and adheres to inflamed brain venules in intravital microscopy experiments. Bioluminescence imaging shows that alpha 4 integrins control ASC accumulation in inflamed CNS. Importantly, we found that ASC cultures produce basic fibroblast growth factor, brain-derived growth factor, and platelet-derived growth factor-AB. Moreover, ASC infiltration within demyelinated areas is accompanied by increased number of endogenous oligodendrocyte progenitors. In conclusion, we show that ASCs have clear therapeutic potential by a bimodal mechanism, by suppressing the autoimmune response in early phases of disease as well as by inducing local neuroregeneration by endogenous progenitors in animals with established disease. Overall, our data suggest that ASCs represent a valuable tool for stem cell-based therapy in chronic inflammatory diseases of the CNS
Retradução comentada de Corinne ou l'Italie de Mme de Staël
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão, Programa de Pós-Graduação em Estudos da Tradução, Florianópolis, 2014.Esta tese, vinculada à linha da "Teoria, crítica e história da tradução" objetiva a retradução comentada de Corinne ou l'Italie (1807) de Madame de Staël. No primeiro capítulo, descrevem-se a vida e as obras da autora, com ênfase para Corinne ou l'Italie, que foi traduzida e retraduzida em outras línguas, principalmente o inglês, italiano e alemão. Em seguida, no capítulo 2, apresenta-se a primeira tradução para o português do Brasil Corina ou a Itália (1945, Edições Cultura). Como terceira etapa, comenta-se a retradução com base nas reflexões teóricas de Berman, Pym, Venuti, Gambier. Apresentam-se exemplos dos aspectos semânticos, culturais, estilísticos presentes ao longo dos XX livros, a partir do original e da retradução. Os comentários do processo de tradução permitem uma frutífera troca literária e cultural e a tradução, o estudo e conhecimento da obra de Madame de Staël, por consequência, enriquecem o cânone da literatura francesa traduzida no Brasil.Abstract : This thesis, linked to the research field "Theory, criticism and history of translation" attempts to do a commented retranslation of Mme de Staël's Corinne ou l'Italie (1807). The first chapter describes the life and the works of the author, with emphasis on Corinne ou l'Italie, which was translated and retranslated into other languages, mainly English, Italian and German. In Chapter 2, the first translation of Corinne ou l'Italie into Brazilina Portuguese (1945, Cultura Printings) is presented. In chapter 3 the retranslation is analyzed through comments based on theoretical reflections of Berman, Pym, Venuti and Gambier. Examples of semantic, cultural and stylistics aspects of the XX books (original and retranslated version) are presented. The comments of the translation process allow a rich literary and cultural exchange. As well as a deeper investigation about Madame de Staël's work enriches the standard of French literature in Brazil
A role for leukocyte-endothelial adhesion mechanisms in epilepsy
No full textThe mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood(1-3). Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins alpha(4)beta(1) and alpha(L)beta(2). Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy
Surrealism, photography and the periodical press: an investigation into the use of photography in surrealist publications (1924 - 1969) with specific reference to themes of sexuality and their interaction with commercial photographic images of the period
No full textThis thesis examines the use of photographs in surrealist publications in Paris between 1924 and 1969, analysing how images functioned both in relation to surrealism and a wider cultural, social and political context. The thesis contends that developments in the illustrated press had a substantial impact on surrealist publications and that commercial photographic practices were both exploited and subverted by the group. I defend this assertion by demonstrating how photographers associated with the surrealist movement in its formative years, were closely involved in the process by which the photographic image became a major means of communication. I argue that the surrealists were conscious that photography was central to the circulation of ideas and developed a radical notion of the illustration of text. The thesis examines how photographs used in surrealist publications were integrated into the complex surrealist project and how due to the currency in images in society, the medium offered opportunities for disruption. In each of the five chapters I examine the surrealist deployment of photographic images to articulate cultural and political radicalism. The thesis argues that the photographs published by the surrealists made an important contribution to contemporary discourse on sexuality This thesis makes an original contribution to knowledge as it expands the understanding of photographs published by the surrealist group by exploring their relationship to contemporary commercial images circulating in the press. It analyses works that have been marginalised, many of the images in the first two journals in the inter war period, the images in the illustrated books 1929, Banalité, Le septième face du dé and the images in the post war journals have been neglected as subjects of study
