Histological Study on Double Line of Intravenous Tacrolimus Infusion in Sla Defined Pig Model

The immunosuppressive therapy still remains the only therapeutic strategy to control excessive immune activation following renal transplantation, but remain the problems related to excessive immunosuppression and in particular the toxicity due to high doses of immunosuppressive drugs such as calcineurin inhibitors. The present study has the aim of documenting, in a porcine animal model, the histological damage from calcineurin inhibitors using incremental doses of Tacrolimus, achieved in a limited amount of time, until it reaches toxic blood concentrations. We perform the study under different condition, like oral administration, intravenous infusion and with or without kidney transplant. It is noted that the damage is early, predominantly vascular and that affects different organs in addition to the kidneys. We also observe that the functional damage underestimates the structural damage. The search for non-invasive methods for the identification of biomarkers of nephrotoxicity and rejection, and to better characterize the inflammation status, led us to conduct analysis of the exosomal content, allowing us to observe the presence of serum cytokines which, although in low amounts, suggest a possible role of these in the inflammatory process mediated by exosomal vesicles. Finally, following the genetic SLA typing for the determination of the donors and the recipients, in an accessory project, we got a controlled and stable colony of pigs with SLA defined in homozygosis through the coupling of specific pathogen free pigs (SPF) for DQB-1 and SLA-1 genes.