Maximizing Vascularized Composite Allograft Survival by only targeting local immune response without impairing the host’s immune system.

Objective: The current standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) involves systemic immunosuppression, which exposes the host to risks like infections and lymphoproliferative disorders due to its systemic distribution. Despite some progress, development of immunosuppression regimens promoting graft survival with minimal side effects has been slow, mainly due to a lack of understanding of the crucial mechanisms behind graft rejection. Here, we aimed to investigate the effect of a locally administered tacrolimus-loaded on-demand drug delivery system in a clinically relevant VCA animal model. Methods: After heterotopic pig limb allotransplantation, animals were either left untreated or received monthly intra-graft injections of a tacrolimus-loaded drug delivery system (DDS). Pigs were then followed up until postoperative day 90 (POD) or grade IV rejection. Skin and blood samples were collected at different time points to evaluate off-target toxicity, tacrolimus levels and the immune response. Results: Treatment with a tacrolimus-based DDS allowed the grafts to survive up to POD90. In contrast, untreated animals rejected around POD 7. Interestingly, tissue levels of tacrolimus in treated animals were significantly higher in injected grafts compared to the contralateral side, indicating local release of tacrolimus, with no signs of systemic off-target toxicity in kidney and liver samples. Surprisingly, no effect in circulating levels of soluble complement, regulatory cytokines and T cell subsets was observed at endpoint when compared to baseline in both groups. Contrarily, a significant decrease in T-cell, B-cell and neutrophil infiltration was quantified intra-graft in animals treated with the DDS compared to untreated pigs. Conclusion: Our preliminary data suggest that by using a tacrolimus-based DDS, graft survival can be prolonged by only dampening the local immune response without impairing the host’s systemic immune system or inducing off-target toxicity. Thus, our developed DDS is a promising alternative to overcome the current challenges in VCA associated with systemic immunosuppression.

Inselspital
Universität Bern