title: Molecular markers and targeted therapy of skin rejection in composite tissue allotransplantation.
abstract: Skin rejection remains a major hurdle in reconstructive transplantation. We investigated molecular markers of skin rejection with particular attention to lymphocyte trafficking. Skin biopsies (n = 174) from five human hand transplant recipients were analyzed for rejection, characteristics of the infiltrate and lymphocytic adhesion markers. The cellular infiltrate predominantly comprised CD3+ T cells. CD68, Foxp3 and indoleamine 2, 3-dioxygenase expression and the CD4/CD8 increased with severity of rejection. Lymphocyte adhesion markers were upregulated upon rejection, intercellular adhesion molecule-1 and E-selectin correlated best with severity of rejection. Guided by the findings, a specific E- and P-selectin inhibitor was investigated for its effect on skin rejection in a rat hind limb allotransplant model. While efomycine M (weekly s.c. injection into the graft) alone had no effect, long-term allograft survival was achieved when combined with antithymocyte globulin and tacrolimus (control group without efomycine M rejected at postoperative day [POD] 61 +/- 1). Upregulation of lymphocyte trafficking markers correlates with severity of skin rejection and time after transplantation in human hand transplantation. Blocking E- and P-selectin in the skin holds potential to significantly prolong limb allograft survival.
authors.affiliation: Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Hautz
authors.forename: B
authors.initials: B
authors.lastname: Zelger
authors.forename: J
authors.initials: J
authors.lastname: Grahammer
authors.forename: C
authors.initials: C
authors.lastname: Krapf
authors.forename: A
authors.initials: A
authors.lastname: Amberger
authors.forename: G
authors.initials: G
authors.lastname: Brandacher
authors.forename: L
authors.initials: L
authors.lastname: Landin
authors.forename: H
authors.initials: H
authors.lastname: Müller
authors.forename: M P
authors.initials: MP
authors.lastname: Schön
authors.forename: P
authors.initials: P
authors.lastname: Cavadas
authors.forename: A W P
authors.initials: AW
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Pratschke
authors.forename: R
authors.initials: R
authors.lastname: Margreiter
authors.forename: S
authors.initials: S
authors.lastname: Schneeberger
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000961:Antilymphocyte Serum / Q000276:immunology; D015415:Biomarkers; D001706:Biopsy; D019040:E-Selectin / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D019007:P-Selectin / Q000276:immunology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D012867:Skin / Q000276:immunology / Q000473:pathology; D016559:Tacrolimus / Q000276:immunology; D013997:Time Factors; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000961:Antilymphocyte Serum; D015415:Biomarkers; D019040:E-Selectin; D018799:Intercellular Adhesion Molecule-1; D019007:P-Selectin; D016559:Tacrolimus; C067980:CD68 antigen, human; D000097382:CD68 Molecule