Biomarker evaluation of face transplant rejection: association of donor T cells with target cell injury

Modern Pathology (2014) 27, 788–799; doi:10.1038/modpathol.2013.249; published online 17 January 2014

Christine Guo Lian, Ericka M Bueno, Scott R Granter, Alvaro C Laga, Arturo P Saavedra, William M Lin, Joseph S Susa, Qian Zhan, Anil K Chandraker, Stefan G Tullius, Bohdan Pomahac and George F Murphy

Recent reports emphasizing the critical therapeutic importance of accurate diagnosis of transplant rejection1 have stressed the imminent need for more precise clinicopathologic criteria and complementary application of relevant biomarkers.2 The first systematic studies of any form of human allograft rejection were reported by Gibson and Medawar3 in their classic description of skin rejection involving wartime aviators.4 Early clues regarding the immunologic basis of skin graft rejection came from studies by Dvorak et al5 and Bhan et al6 that implicated both CD4+ and CD8+ T cells. These T-cell populations were presumed to be of recipient origin and considered to be primary effectors of epidermal and dermal microvascular target cell injury. With the recent advent of full-facial transplantation,7 detailed and sequential histopathologic surveillance for rejection in a manner seldom feasible for conventional skin allografts has become a necessity. However, existing schemas8 for histologic recognition and grading of rejection in vascular composite allotransplantation are based primarily on allografts that may express relevant structural and immunological differences from facial tissues, eg, extremities (hand) and abdominal wall transplantations. Moreover, precise understanding of immune cell phenotypes that participate in rejection phenomena in this emerging frontier remains incomplete. Here, we report a detailed sequential clinicopathological study in five full facial transplant recipients who were successfully treated for rejection. These studies are complemented by biomarker immunophenotyping of three patients who experienced most significant and specific histopathological changes. Serial biopsies in our study revealed lymphocyte-mediated injury of microvessels, stem cell-rich epidermal and follicular microcompartments, and associated target cell apoptosis in anagen follicles that persists after therapy-induced remission. Importantly, T cells with immunophenotypes consistent with donor cells resident to the facial transplants are identified as major constituents of the rejection response, a finding with potentially important diagnostic and therapeutic implications.