Local injections of tacrolimus-loaded hydrogel reduce systemic immunosuppression-related toxicity in vascularized composite allotransplantation

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 naïve 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. Corresponding authors: Adriano Taddeo, Ph.D., Department for BioMedical Research, University of Bern, Murtenstrasse 50, 3008, Bern, Switzerland. Telephone: +41 31 632 02 99. Fax: +41 31 632 75 94. E-Mail: adriano.taddeo@dbmr.unibe.ch; Robert Rieben, Ph.D., Department for BioMedical Research, University of Bern, Murtenstrasse 50, 3008, Bern, Switzerland. Telephone: +41 31 632 96 69. Fax: +41 31 632 75 94. E-Mail: robert.rieben@dbmr.unibe.ch Authorship: D.V.D. performed and analyzed the in vivo experiments, flow cytometry, TGMS-TAC hydrogel preparation, DSA analyses. R.O. and J.L. designed and performed the hind limb transplantations. Y.B. performed and analyzed the histopathological evaluations. J.-C.P. performed the tissue TAC analyses. A.D. and P.K.V. designed and developed the TGMS-TAC hydrogel. D.V.D., A.T. and R.R. wrote the manuscript. E.V., P.K.V., A.T. and R.R. designed and supervised the studies, and reviewed the manuscript. Disclosure: The authors declare no conflicts of interest. Funding: This work was supported by Indo-Swiss Joint Research Program of the Swiss National Science Foundation (SNF, grant 156773) and the Department of Science and Technology, Govt. of India (grant INT/SWISS/SNSFP-51/2015) to R.R., E.V. and P.K.V., respectively. A.D. thanks the University Grant Commission for the senior research fellowship. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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