Vascularized composite allograft transplant survival in miniature swine: is MHC tolerance sufficient for acceptance of epidermis?
BACKGROUND
We have previously reported that Massachusetts General Hospital miniature swine, which had accepted class I-mismatched kidneys long-term after 12 days of high-dose cyclosporine A, uniformly accepted donor-major histocompatibility complex (MHC)-matched kidneys without immunosuppression but rejected donor MHC-matched split-thickness skin grafts by day 25, without changes in renal graft function or antidonor in vitro responses. We have now tested whether this "split tolerance" would also be observed for the primarily vascularized skin of vascularized composite allografts (VCAs).


METHODS
Group 1 animals (n=3) received donor MHC-matched VCAs less than 70 days after primary kidney transplant (KTx). Group 2 animals (n=3) received a second donor-matched kidney transplant followed by a donor-matched VCA more than 200 days after primary KTx.


RESULTS
Animals in Group 1 lost the epidermis on days 28, 30, and 40, with all other components of the VCAs remaining viable. Histology showed cellular infiltration localized to dermal-epidermal junction. One of three recipients of VCAs in Group 2, accepted all components of the VCA, including epidermis (>200 days). The other two recipients lost only the epidermis on days 45 and 85, with survival of the remainder of the VCA long-term.


CONCLUSIONS
All tissues of a VCA are accepted long-term on animals tolerant of class I-mismatched kidneys, with the exception of epidermis, the survival of which is markedly prolonged compared with split-thickness skin grafts but not indefinite. Exposure of tolerant animals to second donor-matched kidneys before VCA increases the longevity of the VCA epidermis, suggesting an increase in the immunomodulatory mechanisms associated with tolerance of the kidney.
1 Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 2 Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 3 Address correspondence to: Kazuhiko Yamada, M.D., Ph.D., Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, MGH-East, Building 149-9014, 13th Street, Boston, MA 02129.
Curtis L
CL
Cetrulo
Radbeh
R
Torabi
Joseph R
JR
Scalea
Akira
A
Shimizu
Angelo A
AA
Leto Barone
Bradford C
BC
Gillon
Masayuki
M
Tasaki
David A
DA
Leonard
Taylor A
TA
Cormack
Vincenzo
V
Villani
Mark A
MA
Randolph
David H
DH
Sachs
Kazuhiko
K
Yamada
D000818:Animals; D064595:Composite Tissue Allografts / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D016572:Cyclosporine / Q000494:pharmacology; D004817:Epidermis / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006648:Histocompatibility; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D016038:Skin Transplantation / Q000009:adverse effects*; D013552:Swine; D013556:Swine, Miniature; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects; D063986:Vascularized Composite Allotransplantation / Q000009:adverse effects*
D007166:Immunosuppressive Agents; D016572:Cyclosporine