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Improved Compliance via Regional Immunosuppression Induces Long-term Survival in Vascularized Composite Allotransplantation
Jignesh Unadkat, MD, MRCS1; Jonas Schnider, MD1; Kacey Marra, PhD1; Mario Solari, MD1; Angus Thomson, PhD2; Alexander Spiess, MD1
1Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, 2Immunology, Transplantation, University of Pittsburgh, Pittsburgh, PA

Background: Initial experience with vascularized composite allotransplantation (VCA) has shown medication non-compliance results in increased acute rejection episodes and ultimately poor long-term outcomes. Delivering immunosuppression to sites of allorecogition and T-cell activation without daily systemic immunosuppression would lead to improved compliance and overall allograft survival without systemic side-effects.

Hypothesis: Fk506 encapsulated microspheres implanted subcutaneously will release thearapeutic Fk506 to maintain VCA without daily Fk506 administration.

Methods: Fk506 was encapsulated in PLGA/PLA microspheres and incorporated into 5mm PLGA discs. Brown-Norway(BN) to Lewis(Lew) functional orthotopic hind-limb transplants were performed. Group1: Systemic Fk (daily Fk506 i.p. for 21days). Group2: 1 Fk disc in allograft. Group3: 1 Fk disc in contralateral native untransplanted leg. End-point 180 days survival or grade3 rejection. Blood FK levels measured at regular intervals. At end-point, blood and allograft tissue Fk levels measured. T cell mixed lymphocytic reaction assays performed at end-point.

Results: There were therapeutic blood Fk levels between 5-15ng/ml for 20, 152, 156 days in group1, 2 and 3 respectively. Following day 150 (+/-6.1), Fk levels were sub therapeutic at <5ng/ml. Allograft survival was 40(+/- 5.1), 156 and >180 days in groups1, 2 and 3 respectively. There were significantly increased Fk506 levels in regional groin lymph nodes on the side where the Fk disc was implanted. Similarly, there was significant blunting in the immune proliferative capacity of the T cells from lymph nodes draining the Fk disc.

Conclusion: Implantation of one Fk disc leads to prolonged survival in VCA without need for daily systemic administration. The Fk506 is concentrated regionally in the draining lymph node and prevents immune activation thereby preventing rejection of the transplanted allograft without need for systemic immunosuppression levels. This strategy would improve compliance following VCA and induce long-term allograft survival without associated side-effects of systemic immunosuppression.

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