Dual and Opposite Costimulatory Targeting with a Novel Human Fusion Recombinant Protein Effectively Prevents Renal Warm Ischemia Reperfusion Injury and Allograft Rejection in Murine Models
| Autor: | Marta Jarque, Alba Torija, Silvia Barcelo-Batllori, Laura de Ramon, David Resina, Nuria Bolaños, Oriol Bestard, Pere Fontova, Laura Martínez-Valenzuela, Josep M. Grinyó, Elena Crespo, Joan Torras, Jordi Guiteras |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Graft Rejection
0301 basic medicine Trasplantament renal SPR Adaptive Immunity Kidney Function Tests Body Temperature Kidney transplantation lcsh:Chemistry Mice 0302 clinical medicine Ischemia Isquèmia Immune Checkpoint Inhibitors innate immunity lcsh:QH301-705.5 Spectroscopy Kidney biology Graft Survival FOXP3 General Medicine Allografts Immunohistochemistry Computer Science Applications medicine.anatomical_structure costimulation Reperfusion Injury 030220 oncology & carcinogenesis protein binding affinity medicine.symptom Signal Transduction kidney transplant Recombinant Fusion Proteins CD3 ischemia-reperfusion injury Inflammation Article Catalysis Proinflammatory cytokine Immunomodulation Inorganic Chemistry 03 medical and health sciences In vivo medicine Animals Physical and Theoretical Chemistry Molecular Biology coinhibition business.industry Organic Chemistry Immune Checkpoint Proteins medicine.disease Kidney Transplantation Immunity Innate Rats Disease Models Animal 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 inflammation Cancer research biology.protein business Reperfusion injury Biomarkers CD80 |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 1216, p 1216 (2021) Dipòsit Digital de la UB Universidad de Barcelona International Journal of Molecular Sciences Volume 22 Issue 3 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | Many studies have shown both the CD28&mdash D80/86 costimulatory pathway and the PD-1&mdash PD-L1/L2 coinhibitory pathway to be important signals in modulating or decreasing the inflammatory profile in ischemia-reperfusion injury (IRI) or in a solid organ transplant setting. The importance of these two opposing pathways and their potential synergistic effect led our group to design a human fusion recombinant protein with CTLA4 and PD-L2 domains named HYBRI. The objective of our study was to determine the HYBRI binding to the postulated ligands of CTLA4 (CD80) and PD-L2 (PD-1) using the Surface Plasmon Resonance technique and to evaluate the in vivo HYBRI effects on two representative kidney inflammatory models&mdash rat renal IRI and allogeneic kidney transplant. The Surface Plasmon Resonance assay demonstrated the avidity and binding of HYBRI to its targets. HYBRI treatment in the models exerted a high functional and morphological improvement. HYBRI produced a significant amelioration of renal function on day one and two after bilateral warm ischemia and on days seven and nine after transplant, clearly prolonging the animal survival in a life-sustaining renal allograft model. In both models, a significant reduction in histological damage and CD3 and CD68 infiltrating cells was observed. HYBRI decreased the circulating inflammatory cytokines and enriched the FoxP3 peripheral circulating, apart from reducing renal inflammation. In conclusion, the dual and opposite costimulatory targeting with that novel protein offers a good microenvironment profile to protect the ischemic process in the kidney and to prevent the kidney rejection, increasing the animal&rsquo s chances of survival. HYBRI largely prevents the progression of inflammation in these rat models. |
| Databáze: | OpenAIRE |
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