Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine.
BACKGROUND
Although transplantation of musculoskeletal allografts in humans is technically feasible, the adverse effects of long-term immunosuppression subject the patient to high risks for correcting a non-life-threatening condition. Achieving immunologic tolerance to musculoskeletal allografts, without the need for chronic immunosuppression, could expand the clinical application of limb tissue allografting. Tolerance to musculoskeletal allografts has been accomplished previously in miniature swine in our laboratory. Although stable, mixed chimerism has been suggested as the mechanism underlying long-term tolerance in a rat limb model, the mechanism of this tolerance induction has not been established. This report explores the possible relationship between hematopoietic chimerism and tolerance to musculoskeletal allografts in swine.


METHODS
Twelve miniature swine underwent vascularized musculoskeletal allograft transplantation from histocompatibility complex (MHC) matched, minor antigen-mismatched donors. Eight animals received a 12-day coprse of cyclosporine, one of which was excluded due to subtherapeutic levels. Four recipients were not immunosuppressed. Serial biopsies to assess graft viability and flow cytometry to assess chimerism were performed. Donor and third-party skin grafts were placed on recipients with surviving allografts greater than 100 days to validate tolerance.


RESULTS
Both groups developed early peripheral chimerism, but this chimerism became undetectable by postoperative day 19 in the cyclosporine group and by day 13 in the control group. Animals receiving cyclosporine developed permanent tolerance to their allografts, whereas those not receiving cyclosporine rejected their allografts in 6-9 weeks. Animals demonstrating tolerance to their bone allografts also demonstrated prolonged donor skin graft survival.


CONCLUSIONS
Induction of tolerance to musculoskeletal allografts can be achieved in the MHC matched swine. Although hematopoietic chimerism is present in the immediate postoperative period, persistent, long-term chimerism does not seem to be necessary for maintenance of such tolerance.
Bourget
J L
JL
Division of Plastic Surgery, Harvard Medical School and Massachusetts General Hospital, Boston 02114, USA.
Mathes
D W
DW
Nielsen
G P
GP
Randolph
M A
MA
Tanabe
Y N
YN
Ferrara
V R
VR
Wu
A
A
Arn
S
S
Sachs
D H
DH
Lee
W P
WP
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis; D002678:Chimera; D005434:Flow Cytometry; D006085:Graft Survival; D006614:Hindlimb; D006648:Histocompatibility; D007108:Immune Tolerance; D008214:Lymphocytes / Q000502:physiology*; D009141:Musculoskeletal System; D016038:Skin Transplantation; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D016378:Tissue Transplantation; D014184:Transplantation, Homologous
D000954:Antigens, Surface