Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
| Autor: | Jordi Guiteras, Elena Crespo, Pere Fontova, Nuria Bolaños, Montse Gomà, Esther Castaño, Oriol Bestard, Josep M. Grinyó, Joan Torras |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Immunoregulació
Mice Inbred MRL lpr Autoimmune diseases Programmed Cell Death 1 Receptor Kidney Catalysis Inorganic Chemistry Immunomodulation Mice Animals Humans Lupus Erythematosus Systemic Physical and Theoretical Chemistry Molecular Biology Spectroscopy Lupus erythematosus Kidney diseases Malalties autoimmunitàries costimulation coinhibition immunomodulation CTLA4 PDL2 systemic lupus erythematosus lupus nephritis glomerulonephritis autoimmunity inflammation Organic Chemistry Immunoregulation General Medicine Lupus Nephritis Recombinant Proteins Computer Science Applications Disease Models Animal Lupus eritematós Antibodies Antinuclear Malalties del ronyó |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 15; Pages: 8411 Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23158411 |
| Popis: | Systemic lupus erythematosus is a complex autoimmune disorder mostly mediated by B-cells in which costimulatory signals are involved. This immune dysregulation can cause tissue damage and inflammation of the kidney, resulting in lupus nephritis and chronic renal failure. Given the previous experience reported with CTLA4-Ig as well as recent understanding of the PD-1 pathway in this setting, our group was encouraged to evaluate, in the NZBWF1 model, a human fusion recombinant protein (Hybri) with two domains: CTLA4, blocking the CD28—CD80 costimulatory pathway, and PD-L2, exacerbating the PD-1–PD-L2 coinhibitory pathway. After achieving good results in this model, we decided to validate the therapeutic effect of Hybri in the more severe MRL/lpr model of lupus nephritis. The intraperitoneal administration of Hybri prevented the progression of proteinuria and anti-dsDNA antibodies to levels like those of cyclophosphamide and reduced the histological score, infiltration of B-cells, T-cells, and macrophages and immune deposition in both lupus-prone models. Additionally, Hybri treatment produced changes in both inflammatory-related circulating cytokines and kidney gene expression. To summarize, both in vivo studies revealed that the Hybri effect on costimulatory-coinhibitory pathways may effectively mitigate lupus nephritis, with potential for use as a maintenance therapy. |
| Databáze: | OpenAIRE |
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