Tolerance to composite tissue allografts across a major histocompatibility barrier in miniature swine.
BACKGROUND
Tolerance to composite tissue allografts might allow the widespread clinical use of reconstructive allotransplantation if protocols to achieve this could be rendered sufficiently nontoxic. The authors investigated whether tolerance could be generated in miniature swine to composite tissue allografts across a major histocompatibility (MHC) barrier. A clinically relevant tolerance protocol involving hematopoietic cell transplantation without the need for irradiation or myelosuppressive drugs was tested.


METHODS
Seven recipient animals were transiently T-cell depleted and a short course of cyclosporine was initiated. Twenty-four hours later, a donor hematopoietic cell transplant consisting of cytokine-mobilized peripheral blood mononuclear cells or bone marrow cells and a heterotopic limb transplant were performed. In vitro anti-donor responsiveness was assessed by mixed-lymphocyte reaction and cell-mediated lympholysis assays. Acceptance of the limb allografts was determined by gross and histologic appearance. Chimerism in the peripheral blood and lymphohematopoietic organs was assessed by flow cytometry.


RESULTS
All seven experimental animals accepted the musculoskeletal elements but rejected the skin of the allografts. All but one of the animals displayed donor-specific unresponsiveness in vitro. The animals that received cytokine mobilized-peripheral blood mononuclear cells showed chimerism but had clinical evidence of graft-versus-host disease (GVHD). None of the animals that received bone marrow cells showed stable chimerism and none developed GVHD.


CONCLUSIONS
This protocol can achieve tolerance to the musculoskeletal elements of composite tissue allografts across an MHC barrier in miniature swine. Stable chimerism does not appear to be necessary for tolerance and may not be desirable because of the risk of GVHD.
Hettiaratchy
Shehan
S
Division of Plastic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. shehan_h@hotmail.com
Melendy
Elizabeth
E
Randolph
Mark A
MA
Coburn
Rebecca C
RC
Neville
David M
DM
Sachs
David H
DH
Huang
Christene A
CA
Lee
W P Andrew
WP
D000818:Animals; D001787:Blood Group Incompatibility; D001842:Bone and Bones / Q000503:physiopathology; D006084:Graft Rejection; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000453:epidemiology; D018380:Hematopoietic Stem Cell Transplantation; D006614:Hindlimb / Q000503:physiopathology / Q000637:transplantation*; D015994:Incidence; D012867:Skin / Q000503:physiopathology; D013552:Swine; D013556:Swine, Miniature; D018183:Transplantation Chimera; D023001:Transplantation Tolerance