CD40 gene silencing reduces the progression of experimental lupus nephritis modulating local milieu and systemic mechanisms.
| Autor: | Èlia Ripoll, Ana Merino, Immaculada Herrero-Fresneda, Josep M Aran, Montse Goma, Nuria Bolaños, Laura de Ramon, Oriol Bestard, Josep M Cruzado, Josep M Grinyó, Juan Torras |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | PLoS ONE, Vol 8, Iss 6, p e65068 (2013) |
| Druh dokumentu: | article |
| ISSN: | 1932-6203 99213346 |
| DOI: | 10.1371/journal.pone.0065068 |
| Popis: | 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 insterstitial CD3+ 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. |
| Databáze: | Directory of Open Access Journals |
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