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Topical Immunotherapy Synergizes with Systemic Immunotherapy to Prolong Survival of Vascularized Composite Allografts without Morbid Adverse Effects
Firuz G. Feturi, B. Pharm., PhD, Vasil E. Erbas, MD, Liwei Dong, MD, Huseyin Sahin, MD, Wensheng Zhang, MD, Alexander Spiess, MD, Mario Solari, MD, Raman Venkatramanan, PhD, Vijay S. Gorantla, MD., PhD.
University of Pittsburgh, Pittsburgh, PA, USA.

Systemic tacrolimus (STAC) has proven efficacy in management of acute rejection (AR) in VCA, but commonly causes hyperglycemia and nephrotoxicity. Alternative therapies to avoid both the acute rejection and the complications of the life-long systemic TAC are needed. Vascularized Composite Allografts (VCA) provides a unique opportunity for the local delivery of the drugs directly to the graft. Topical TAC (TTAC) preferentially concentrates in VCA graft tissues with minimal systemic exposure but fails to prevent AR when used alone. We evaluated whether topical delivery of TAC and MPA was synergistic with STAC in preventing/treating AR while reducing the dosing needs of STAC and its associated metabolic complications.
Brown Norway -to- Lewis rat orthotopic hind limb allotransplants (6/group) were performed and received STAC (1mg/kg/day, IP) for 7 days. On POD 8, STAC dose was maintained at 1 mg/kg for Group 1, and dropped to 0.1mg/kg for Group 2. Topical application of no treatment (Control, Group 3), TAC 0.5mg/kg/day (Group 4), MPA 1.6mg/kg/day (Group 5), and a combination of two topical formulations (Group 6) were initiated at day 8 to overlap with STAC (0.1mg/kg/day). Treatment was continued until Grade III rejection. Tail vein sampling was performed weekly. Trough levels of TAC and MPA was analyzed by HPLC-MS. Tissue biopsies were collected for drug levels measurement, cytokines analysis, and histopathology. In addition to allograft survival, systemic toxicity was evaluated using percent change in body weight (BW), glycaemia, and creatinine clearance (CrCl).
Best outcomes were obtained in group treated with a combination of the two topical formulations in a conjunction with low dose of systemic immunotherapy (Allograft Survival > 100 days). Drugs levels were low or undetectable in blood and/or plasma, whereas drug levels were significantly higher in VCA tissues compared to blood levels (P<0.05). Percent change in BW, glycaemia, and 24 hr urinary creatinine clearance were in the normal range (<±15%, 80-120mg/dl, and 2.5 ml/min). Histological evaluation was correlated with the clinical sign of rejection.
We conclude that topical delivery of TAC and MPA is synergistic to STAC in reducing systemic morbidity while facilitating AR free VCA survival. This will participate not only to shift the current research paradigms of the use of systemic immunosuppression to local immunosuppression by using topical immunotherapy, but also to establish the basis to develop site-specific formulations to targeted immunosuppressive drug delivery.

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