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CD40 gene silencing reduces the progression of experimental lupus nephritis modulating local milieu and systemic mechanisms
Ripoll Llagostera, Èlia; Merino, Ana; Gomà, Montse; Aran Perramon, Josep M.; Bolaños, Nuria; Ramon, Laura de; Herrero Fresneda, Immaculada; Bestard Matamoros, Oriol; Cruzado, Josep Ma.; Grinyo Boira, Josep M.; Torras Ambròs, Joan
Lupus nephritis (LN) is an autoimmune disorder in which co-stimulatory signals have been involved. Here we tested a cholesterol-conjugated-anti-CD40-siRNA in dendritic cells (DC) in vitro and in a model of LPS to check its potency and tissue distribution. Then, we report the effects of Chol-siRNA in an experimental model of mice with established lupus nephritis. Our in vitro studies in DC show a 100%intracellular delivery of Chol-siRNA, with a significant reduction in CD40 after LPS stimuli. In vivo in ICR mice, the CD40-mRNA suppressive effects of our Chol-siRNA on renal tissue were remarkably sustained over a 5 days after a single preliminary dose of Chol-siRNA. The intra-peritoneal administration of Chol-siRNA to NZB/WF1 mice resulted in a reduction of anti-DNA antibody titers, and histopathological renal scores as compared to untreated animals. The higher dose of Chol-siRNA prevented the progression of proteinuria as effectively as cyclophosphamide, whereas the lower dose was as effective as CTLA4. Chol-siRNA markedly reduced insterstitialCD3+ and plasma cell infiltrates as well as glomerular deposits of IgG and C3. Circulating soluble CD40 and activated splenic lymphocyte subsets were also strikingly reduced by Chol-siRNA. Our data show the potency of our compound for the therapeutic use of anti-CD40-siRNA in human LN and other autoimmune disorders.
Malalties del ronyó
RNA
Kidney diseases
RNA
cc-by (c) Ripoll Llagostera, Èlia et al., 2013
http://creativecommons.org/licenses/by/3.0/es
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Ripoll Llagostera, Èlia; Merino, Ana; Gomà, Montse; Aran Perramon, Josep M.; Bolaños, Nuria; Ramon, Laura de; Herrero Fresneda, Immaculada; Bestard Matamoros, Oriol; Cruzado, Josep Ma.; Grinyo Boira, Josep M.; Torras Ambròs, Joan
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Crespo, Elena; Lucia, Marc; Cruzado, Josep Ma.; Luque, Sergio; Melilli, Edoardo; Manonelles, Anna; Lloberas Blanch, Núria; Torras Ambròs, Joan; Grinyo Boira, Josep M.; Bestard Matamoros, Oriol