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

Abstract

This series of 113 sequential biopsies of full facial transplants provides findings of potential translational significance as well as biological insights that could prompt reexamination of conventional paradigms of effector pathways in skin allograft rejection. Serial biopsies before, during, and after rejection episodes were evaluated for clinicopathological assessment that in selected cases included specific biomarkers for donorversus-recipient T cells. Histologic evidence of rejection included lymphocyte-associated injury to epidermal rete ridges, follicular infundibula, and dermal microvessels. Surprisingly, during active rejection, immune cells spatially associated with target cell injury consisted abundantly or predominantly of lymphocytes of donor origin with an immunophenotype typical of the resident memory T-cell subset. Current dogma assumes that skin allograft rejection is mediated by recipient T cells that attack epidermal targets, and the association of donor T cells with sites of target cell injury raises questions regarding the potential complexity of immune cell interactions in the rejection process. A more histopathologically refined and immune-based biomarker approach to assessment of rejection of facial transplants is now indicated. Modern Pathology (2014) 27, 788-799; doi:10.1038/modpathol.2013.249; published online 17 January 2014Keywords: donor T cell; facial transplant; graft-versus-host disease; skin allograft; T resident memory cells; vascularized composite allotransplantation Recent reports emphasizing the critical therapeutic importance of accurate diagnosis of transplant rejection 1 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 Medawar 3 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 al 5 and Bhan et al 6 that implicated both CD4 þ and CD8 þ 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 fullfacial transplantation, 7 detailed and sequential histopathologic surveillance for rejection in a manner seldom feasible for conventional skin allografts has become a necessity. However, existing schemas 8 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

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

“…CD8 + T‐cells mediate epidermal involvement, with the CD4 + subtype mainly associated with dermal interactions. These T‐cell populations are presumed to originate from the recipient and have the ability to cause injury to epidermal and dermal microvascular target cells (Lian et al, ). Our IHC study demonstrated the clinical rejection status decreased after application of topical immunosuppressant drugs, which correlated with T cell expressions.…”

Immunobiology in VCA

“…However, a study published recently by Lian et al . demonstrates this may not be the case in VCA allografts. The finding by Clark et al .…”

“…that normal skin contains twice as many T effector cells as in the peripheral blood suggests that the donor skin should be home to many donor T cells, even after the transplant. In a study of 113 biopsies from face transplant recipients, during active rejection, the majority of the lymphocytes spatially associated with areas of injury were of donor rather than recipient origin . Additionally, most of these donor lymphocytes are CD8+, and of a T resident memory (T RM ) phenotype.…”

Accommodation and related conditions in vascularized composite allografts

“…Recipient blood vessels clearly can and do present donor peptide in MHC, which allo-specific T cells recognize, infiltrate and trigger CMR. VCA are also found to contain numerous, possibly expanded populations of donor T cells (16, 36, 37). Whether donor-derived T cells attack blood vessels of recipient origin that grow into VCA is unknown, but a question of potential import since donor T cells presumably are less subject to control by induction regimens.…”