Molecular markers and targeted therapy of skin rejection in composite tissue allotransplantation.
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.
Hautz
T
T
Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Innsbruck Medical University, Innsbruck, Austria.
Zelger
B
B
Grahammer
J
J
Krapf
C
C
Amberger
A
A
Brandacher
G
G
Landin
L
L
Müller
H
H
Schön
M P
MP
Cavadas
P
P
Lee
A W P
AW
Pratschke
J
J
Margreiter
R
R
Schneeberger
S
S
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
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