Browsing by Author "Gutierrez, Miguel A."

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    Genetic and pharmacological modulation of dendritic cell-T cell interactions as a therapeutic strategy for systemic lupus erythematosus.
    (2011) Llanos, Carolina; Carreno, Leandro J.; Gutierrez, Miguel A.; Riedel, Claudia A.; Jacobelli, Sergio H.; Kalergis, Alexis M.
    Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by an excessive production of auto-antibodies against double-stranded DNA, nucleosomes, ribonucleoproteins and other nuclear components. Accumulation of self-reactive antibodies leads to immune complex deposition in blood vessels, activation of macrophages and complement, inflammation and subsequent tissue damage in several organs, such as the heart, kidneys, lungs and central nervous system. Although significant progress has been made in the past 30 years of research, no effective specific treatments are currently available. The course of this disease remains unpredictable and patients diagnosed with SLE face long-term treatments with the subsequent economic, social and health burden. From the immunological perspective, SLE is a genetic- and environment-controlled disease that involves almost every constituent of the immune system, including both innate and adaptive immunity. Therefore, several immune cell types and molecules could be susceptible for intervention and modulation to develop more effective and specific treatments. More importantly, such therapies are likely not to induce complete immunosuppression and show reduced side effects on patients. In this article we discuss recent work in the field of SLE pathogenesis with a focus on data that provide clues for therapy design and new treatments.
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    Haem oxygenase 1 expression is altered in monocytes from patients with systemic lupus erythematosus
    (WILEY, 2012) Herrada, Andres A.; Llanos, Carolina; Mackern Oberti, Juan P.; Carreno, Leandro J.; Henriquez, Carla; Gomez, Roberto S.; Gutierrez, Miguel A.; Anegon, Ignacio; Jacobelli, Sergio H.; Kalergis, Alexis M.
    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple functional alterations affecting immune cells, such as B cells, T cells, dendritic cells (DCs) and monocytes. During SLE, the immunogenicity of monocytes and DCs is significantly up-regulated, promoting the activation of self-reactive T cells. Accordingly, it is important to understand the contribution of these cells to the pathogenesis of SLE and the mechanisms responsible for their altered functionality during disease. One of the key enzymes that control monocyte and DC function is haem oxygenase-1 (HO-1), which catalyses the degradation of the haem group into biliverdin, carbon monoxide and free iron. These products possess immunosuppressive and anti-inflammatory capacities. The main goal of this work was to determine HO-1 expression in monocytes and DCs from patients with SLE and healthy controls. Hence, peripheral blood mononuclear cells were obtained from 43 patients with SLE and 30 healthy controls. CD14+ monocytes and CD4+ T cells were sorted by FACS and HO-1 expression was measured by RT-PCR. In addition, HO-1 protein expression was determined by FACS. HO-1 levels in monocytes were significantly reduced in patients with SLE compared with healthy controls. These results were confirmed by flow cytometry. No differences were observed in other cell types, such as DCs or CD4+ T cells, although decreased MHC-II levels were observed in DCs from patients with SLE. In conclusion, we found a significant decrease in HO-1 expression, specifically in monocytes from patients with SLE, suggesting that an imbalance of monocyte function could be partly the result of a decrease in HO-1 expression.
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    Inhibition of nuclear factor-kappa B enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in experimental autoimmune encephalomyelitis
    (AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2006) Iruretagoyena, Mirentxu I.; Sepulveda, Sofia E.; Lezana, J. Pablo; Hermoso, Marcela; Bronfman, Miguel; Gutierrez, Miguel A.; Jacobelli, Sergio H.; Kalergis, Alexis M.
    Autoimmune disorders develop as a result of deregulated immune responses that target self-antigens and cause destruction of healthy host tissues. Because dendritic cells (DCs) play an important role in the maintenance of peripheral immune tolerance, we are interested in identifying means of enhancing their therapeutic potential in autoimmune diseases. It is thought that during steady state, DCs are able to anergize potentially harmful T cells bearing T cell receptors that recognize self-peptide-major histocompatibility complexes. The tolerogenic capacity of DCs requires an immature phenotype, which is characterized by a reduced expression of costimulatory molecules. On the contrary, activation of antigen-specific naive T cells is enhanced by DC maturation, a process that involves expression of genes controlled by the transcription factor nuclear factor (NF)-kappa B. We evaluated the capacity of drugs that inhibit NF-kappa B to enhance the tolerogenic properties of immature DCs in the experimental autoimmune encephalomyelitis (EAE) model. We show that andrographolide, a bicyclic diterpenoid lactone, and rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, were able to interfere with NF-kappa B activation in murine DCs. As a result, treated DCs showed impaired maturation and a reduced capacity to activate antigen-specific T cells. Furthermore, NF-kappa B-blocked DCs had an enhanced tolerogenic capacity and were able to prevent EAE development in mice. The tolerogenic feature was specific for myelin antigens and involved the expansion of regulatory T cells. These data suggest that NF-kappa B blockade is a potential pharmacological approach that can be used to enhance the tolerogenic ability of immature DCs to prevent detrimental autoimmune responses.
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    Modulation of nuclear factor-kappa B activity can influence the susceptibility to systemic lupus erythematosus
    (WILEY-BLACKWELL PUBLISHING, INC, 2009) Kalergis, Alexis M.; Iruretagoyena, Mirentxu I.; Barrientos, Magaly J.; Gonzalez, Pablo A.; Herrada, Andres A.; Leiva, Eduardo D.; Gutierrez, Miguel A.; Riedel, Claudia A.; Bueno, Susan M.; Jacobelli, Sergio H.
    P>Autoimmune diseases, such as systemic lupus erythematosus (SLE), result from deficiencies in self-antigen tolerance processes, which require regulated dendritic cell (DC) function. In this study we evaluated the phenotype of DCs during the onset of SLE in a mouse model, in which deletion of the inhibitory receptor Fc gamma RIIb leads to the production of anti-nuclear antibodies and glomerulonephritis. Splenic DCs from Fc gamma RIIb-deficient mice suffering from SLE showed increased expression of co-stimulatory molecules. Furthermore, diseased mice showed an altered function of the nuclear factor-kappa B (NF-kappa B) transcription factor, which is involved in DC maturation. Compared with healthy animals, expression of the inhibitory molecule I kappa B-alpha was significantly decreased in mice suffering from SLE. Consistently, pharmacological inhibition of NF-kappa B activity in Fc gamma RIIb-deficient mice led to reduced susceptibility to SLE and prevented symptoms, such as anti-nuclear antibodies and kidney damage. Our data suggest that the occurrence of SLE is significantly influenced by alterations of NF-kappa B function, which can be considered as a new therapeutic target for this disease.