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Topical Immunosuppression Synergizes with Systemic Therapy to Prolong Survival of Vascularized Composite Allografts (VCA) without Morbid Adverse Effects
Firuz Feturi1, Vasil Erbas2, Liwei Dong2, Huseyin Sahin2, Matthias Waldner2, Lin Hu2, Wensheng Zhang 2, Alexander Spiess2, Mario Solari2, Raman Venkatramanan1, Vijay Gorantla2.
1 Department of Pharmaceutical Science, University of Pittsburgh School of Medicine, Pittsburgh, PA
2016-02-01
Presenter: Firuz G. Feturi
Affidavit:
I certify that the material proposed for presentation in this abstract has not been published in any scientific journal or previously presented at a major meeting. The program director is responsible for making a statement within the confines of the box below specific to how much of the work on this project represents the original work of the resident. All authors/submitters of each abstract should discuss this with their respective program director for accurate submission of information as well as the program director's approval for inclusion of his/her electronic signature.
Director Name: Vijay S. Gorantla
Author Category: Medical Student
Presentation Category: Basic Science Research
Abstract Category: Hand
PURPOSE
Systemic tacrolimus (STAC) has proven efficacy in management of acute rejection (AR) in VCA, but commonly causes hyperglycemia and nephrotoxicity. Topical TAC (TTAC) preferentially concentrates in VCA graft tissues with minimal systemic exposure but fails to prevent AR when used alone. We evaluated whether TTAC was synergistic with STAC in preventing/treating AR while reducing the dosing needs of STAC and its associated metabolic complications.
METHOD
Following limb VCA, rats in Group 1 and 2 (n=4/group) were treated with 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. Group 3 (syngeneic) received no treatment. Group 4 were treated with TTAC (0.5mg/kg/day) plus STAC (0.1mg/kg/day). Allograft survival, body weight (BW), glycaemia, and creatinine clearance (CrCl) was evaluated at POD 1 and 30.
RESULTS
Group 1 had 100% allograft survival. 80% of Group 2 showed grade III AR on POD 30 while 80% of animals in Group 4 were rejection-free until POD 100. Group 1 showed 2-fold decrease in BW than other groups. Glucose levels were higher in Group 1 compared to Groups 2 and 3 (120.9±14 vs. 111.8±13 and 99.75±5 mg/dl). A significant decrease in CrCl was observed in Group 1 compared to Groups 2 and 3 (1.3 vs. 2.4 and 2.8 ml/min). Group 4 showed high VCA tissue TAC levels with low blood levels.
CONCLUSION
We conclude that TTAC is synergistic to STAC in reducing systemic morbidity while facilitating AR free VCA survival.
