@article {1189, title = {Local injections of tacrolimus-loaded hydrogel reduce systemic immunosuppression-related toxicity in vascularized composite allotransplantation.}, journal = {Transplantation}, year = {2018}, month = {2018 May 23}, abstract = {

BACKGROUND: Routine application of vascularized composite allotransplantation (VCA) is hampered by immunosuppression-related health comorbidities. To mitigate these we developed an inflammation-responsive hydrogel for local immunosuppression. Here we report on its long-term effect on graft survival, immunological and toxicological impact.

METHODS: Brown Norway-to-Lewis rat hind limb transplantations were treated either systemically with daily injections of 1 mg/kg tacrolimus or with subcutaneous intragraft injections of hydrogel containing 7 mg tacrolimus, every 70 days. Animals were monitored for rejection or other pathology for 280 days. Systemic and graft tacrolimus levels, regulatory T cells, and donor cell chimerism were measured periodically. At endpoint, markers for kidney, liver and metabolic state were compared to na{\"\i}ve age-matched rats.

RESULTS: Both daily systemic tacrolimus and subcutaneous intragraft tacrolimus hydrogel at 70 day intervals were able to sustain graft survival for \>280 days in 5 out of 6 recipients. In the hydrogel group, 1 graft progressed to grade 3 rejection at postoperative day (POD) 149. In systemic tacrolimus group, 1 animal was euthanized due to lymphoma on POD 275. Hydrogel treatment provided stable graft- and reduced systemic tacrolimus levels, and a 4 times smaller total tacrolimus dose compared with systemic immunosuppression. Hydrogel-treated animals showed preserved kidney function, absence of malignancies or opportunistic infections and increased hematopoietic chimerism compared to systemic immunosuppression.

CONCLUSIONS: Our findings demonstrate that localized immunosuppression with tacrolimus hydrogel is a long-term safe and reliable treatment. It may reduce the burden of systemic immunosuppression in VCA, potentially boosting the clinical application of this surgical intervention.

}, issn = {1534-6080}, doi = {10.1097/TP.0000000000002283}, author = {Dzhonova, Dzhuliya V and Olariu, Radu and Leckenby, Jonathan and Banz, Yara and Prost, Jean-Christophe and Dhayani, Ashish and Vemula, Praveen K and Voegelin, Esther and Taddeo, Adriano and Rieben, Robert} }