RESUMO
Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.
RESUMO
BACKGROUND: Alemtuzumab (AZ) is a monoclonal anti-CD52 antibody used as an induction agent in organ transplantation. Few studies have analyzed this agent in the context of simultaneous kidney-pancreas transplantation (SPKT). METHODS: We examined US registry data of SPKT recipient outcomes from January 2002 to October 2009 stratified by induction agent including AZ, other T-cell-depleting agents combined (T cell), IL2 receptor blockade (IL-2RAb), and no induction (none). RESULTS: Of 6860 SPKT recipients, induction therapy was AZ in 10%, T cell in 49%, IL-2RAb in 18%, and none in 22%. On multivariate analysis, there were no significant differences in overall patient survival, pancreas or renal allograft survival, or delayed renal graft function for the three induction groups compared with no induction. Rehospitalization within six months of transplantation occurred more often with AZ (51%) T cell (52%), and IL-2RAB (45%) compared with none (41%; p < 0.0001). On multivariate analysis, there was a significant higher odds of six-month rehospitalization with AZ (aOR 1.40, 95%CI 1.14-1.71), IL-2RAb (aOR 1.20, 95%CI 1.01-1.42-1.20), and other T-cell-depleting agents (aOR 1.50, 95%CI 1.31-1.73) compared with none. Median length of stay was significantly shorter in the AZ (8 d) compared with the IL-2RAb (9 d), T cell (10 d), and none (10 d) groups (p < 0.0001). CONCLUSIONS: There are no differences in patient, pancreas or renal allograft survival using AZ induction. AZ may confer an advantage in the perioperative period as evidenced by a decreased hospital length of stay. However, this benefit may be lost due to more frequent rehospitalizations.