Floor plan - 2013 Annual Meeting - American Association for Hand ...

Local Immunotherapy Inhibits Skin Rejection in Composite Tissue Allotransplantation
Institution where the work was prepared: University of Pittsburgh, Pittsburgh, PA, USA
Mario G. Solari, MD; Kia M. McLean; Justin M. Sacks; Theresa Hautz; Jignesh V. Unadkat; Elaine K. Horibe; Vijay S.
Gorantla; Stefan Schneeberger; Angus W. Thomson; W.P. Andrew Lee; University of Pittsburgh
INTRODUCTION:
Skin is the most immunogenic component of a composite tissue allograft (CTA). Clinically this has manifested as multiple acute skin
rejection episodes in most of the human CTA performed to date. Intravenous steroids and increased systemic immunosuppression have
been used to mitigate these rejection episodes. These drugs cause direct organ toxicity and are associated with metabolic dysfunction,
opportunistic infection, and malignancy. Topical immunotherapy is an attractive and practical therapeutic option to provide local
immunosuppression with minimal systemic toxicity. Topical tacrolimus is known to reduce the stimulatory activity of antigen presenting
cells (APC) toward autologous T cells in atopic dermatitis. The present study applies these properties to CTA. It investigates the potential
of topical tacrolimus to maintain a CTA after total withdrawal of a short course of systemic therapy.
METHOD:
Wistar Furth to Lewis (full MHC mismatch) orthotopic hind limb transplants were performed. Groups included: I- topical tacrolimus
alone, II- anti-lymphocyte serum (ALS) (0.5mL x2 doses) + 21 days cyclosporine (CsA) (10/mg/kg/day), III- ALS (2 doses) + 21 days CsA
+ topical tacrolimus once daily. The endpoint of the study is grade 3 rejection, defined by epidermolysis, or 100 days (long term survival).
Biopsies of skin, muscle, and bone were taken for immunohistochemistry and H&E.
RESULTS:
All animals in Group I (n=7) developed grade 3 clinical rejection by postoperative day (POD) 9, similar to controls without treatment. The
mean onset of grade 3 rejection was POD 40 with a range of 34-44 in Group II (n=7). In Group III (n=6), two animals developed grade 3
rejection on POD 35 and 56. The remaining 4 experimental animals reached the 100 day endpoint without grade 3 rejection (Fig 1).
CONCLUSION:
This study demonstrates the feasibility of maintaining a CTA on topical tacrolimus therapy alone after induction therapy. The induction
protocol in this model mirrors what is currently performed clinically where recipients undergo lymphoid depletion before organ transplantation,
followed by systemic immunosuppression. Preoperative depletion of T cells with ALS, along with a short course of systemic
immunosuppression, prevents acute rejection, while topical tacrolimus may inhibit immune cell activation and multiplication in the skin
component of the CTA. This novel regimen could reduce or eliminate the morbidity associated with systemic immunosuppression in
clinical CTA.
95