Site-Specific Immunosuppression in Vascularized Composite Allotransplantation: Prospects and Potential

Abstract

Skin is the most immunogenic component of a vascularized composite allograft (VCA) and is the primary trigger and target of rejection. The skin is directly accessible for visual monitoring of acute rejection (AR) and for directed biopsy, timely therapeutic intervention, and management of AR. Logically, antirejection drugs, biologics, or other agents delivered locally to the VCA may reduce the need for systemic immunosuppression with its adverse effects. Topical FK 506 (tacrolimus) and steroids have been used in clinical VCA as an adjunct to systemic therapy with unclear beneficial effects. However, there are no commercially available topical formulations for other widely used systemic immunosuppressive drugs such as mycophenolic acid, sirolimus, and everolimus. Investigating the site-specific therapeutic effects and efficacy of systemically active agents may enable optimizing the dosing, frequency, and duration of overall immunosuppression in VCA with minimization or elimination of long-term drug-related toxicity.

Topical tacrolimus and steroids modulate T cells in acute rejection of hand allotransplantation: Two case reports

“…In preclinical studies, topical tacrolimus has been demonstrated to improve graft survival in rodent hind‐limb allograft and face transplantation models (Jablecki, Kaczmarzyk, Patrzalek, Chelmonski, & Domanasiewicz, ; Mastroianni et al, ). In addition, it can significantly increase the local drug concentration without increasing the drug concentration in the blood (Schnider et al, ). The mechanism may be explained as depletion of inflammatory dendritic epidermal cells or reduction of apoptosis‐induced T cells.…”

Vascularized composite allotransplantation: current standards and novel approaches to prevent acute rejection and chronic allograft deterioration

“…In the case of steroid‐resistant ARs, ATG and alemtuzumab reversed all reported episodes successfully. Some centers have also used topical treatment with skin ointments and mouth flushes to treat rejection . However, these applications have not yet been proven to provide a benefit over systemic treatment alone.…”

“…The efficacy of local immunosuppression in clinical VCA remains controversial. Topical treatments with tacrolimus and clobetasol ointments have achieved sufficient resolution of low‐grade (Banff Grade 1 to 1–2) rejections . Preclinical studies of topical tacrolimus and clobetasol demonstrated a benefit for allograft survival in rodent hindlimb and hemi‐face VCA models .…”

Clinical Considerations for Vascularized Composite Allotransplantation of the Eye

“…31,32 Biomimetic sustained release formulations for suppressing composite tissue transplant rejection are particularly appealing for eye transplantation given the precedent for successful similar practices in clinical ophthalmology using dexamethasone intravitreal implants in the treatment of vitreoretinal eye disease. 33 …”