Single Implantable FK506 Disk Prevents Rejection in Vascularized Composite Allotransplantation

Abstract

Sustained regional immunosuppression (with a single FK506 disk) maintained the allograft by means of a high regional concentration of FK506. Notably, this was achieved at subtherapeutic blood concentrations of FK506, without any further systemic FK506 administration.

Evaluation of PLGA microspheres with triple regimen on long‐term survival of vascularized composite allograft – an experimental study

“…Histological evaluation of the muscles and skin obtained from the FK506/MMF/PDNN‐PLGA MS group showed only mild cellular infiltration, compared with severe disruption of tissue architecture and intense monocyte infiltration in the control and MS groups. These observations are consistent with previous reports , yet quite different from a study by Hautz et al in which tacrolimus (FK506) was ceased after PODs 50, and intensive infiltration and necrosis were noticed in the rejected graft skin and muscle at PODs 60.…”

“…Compared with a previous report where 7 mg of FK506 encapsulated in enzyme‐responsive hydrogel was used to achieve more than 100 days of MST , we achieved longer‐term graft survival with lesser amount of FK506 combined with MMF and PDNN. In another study, 40 mg tablets of FK506 resulted in more than 180 days graft survival time . It is clear that our sustained release system with reduced drug dosage was effective in achieving similar MST and also reduced the occurrence of adverse side effects.…”

“…Therefore, newer strategies should be explored to reduce adverse side effects and improve patient compliance. Currently, studies have confirmed that longterm immunosuppression can be achieved with biodegradable tacrolimus disk [12] and enzyme-responsive hydrogel [13] in rat hind limb transplantation model. Biodegradable polymers are particularly interesting as a drug delivery system due to the predictable biodegradability, ease of fabrication, ability to encapsulate a variety of drugs, and relatively stable and sustained release characteristics [9][10][11].…”

“…Following that, a long‐term lowering and flatting of plasma drug concentration curves and relatively high skin and muscle drug concentration occurred at the later time points, which is ideal in the latter stage as low toxicity might be related to low plasma drug level. However, high plasma levels with daily fluctuation were observed in intermittent oral administration group . This may be due to the fact that injecting FK506/MMF/PDNN‐PLGA MS can first released drugs into the graft tissue and then into the blood, while in oral administration, drugs are first absorbed into the blood and then transported to the graft tissue.…”

In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation

“…In summary, the current approach to inducing allograft tolerance by T reg recruitment via local sustained release of a chemokine (CCL22) represents a marked departure from conventional immunosuppression regimens for VCA, as well as many recent experimental approaches involving sustained and/or local delivery of the same immunosuppressive agents currently administered systemically in the clinic (37,38). By inducing dominant alloantigen-specific tolerance without suppressing systemic immune responses (as evidenced by functional conventional T cells in long-term surviving allograft recipients treated with two doses of Recruitment-MP), our novel therapeutic approach has the potential to prevent allograft rejection and avoid patient compliance and toxicity issues associated with current long-term immunosuppression regimens, which also leave patients immunocompromised and unable to fight infections and malignancies.…”