Prolonged survival of composite facial allografts in non-human primates associated with posttransplant lymphoproliferative disorder.
BACKGROUND
Composite tissue allotransplantation may have different immunosuppressive requirements and manifest different complications compared with solid organ transplantation. We developed a non-human primate facial composite tissue allotransplantation model to investigate strategies to achieve prolonged graft survival and immunologic responses unique to these allografts.


METHODS
Composite facial subunits consisting of skin, muscle, and bone were heterotopically transplanted to mixed lymphocyte reaction-mismatched Cynomolgus macaques. Tacrolimus monotherapy was administered via continuous intravenous infusion for 28 days then tapered to daily intramuscular doses.


RESULTS
Five of the six animals treated with tacrolimus monotherapy demonstrated rejection-free graft survival up to 177 days (mean, 113 days). All animals with prolonged graft survival developed posttransplant lymphoproliferative disorders (PTLD). Three animals converted to rapamycin after 28 days of rejection of their allografts, but did not develop PTLD. Genotypic analysis of PTLD tumors demonstrated donor origin in three of the five analyzed by short-tandem repeats. Sustained alloantibodies were detected in rejecting grafts and absent in nonrejecting grafts.


CONCLUSIONS
Tacrolimus monotherapy provided prolonged rejection-free survival of composite facial allografts in a non-human primate model but was associated with the development of a high frequency of donor-derived PTLD tumors. The transplantation of a large volume of vascularized bone marrow in composite tissue allografts may be a risk factor for PTLD development.
Barth
Rolf N
RN
Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD, USA. rbarth@smail.umaryland.edu
Nam
Arthur J
AJ
Stanwix
Matthew G
MG
Kukuruga
Debra
D
Drachenberg
Cinthia I
CI
Bluebond-Langner
Rachel
R
Hui-Chou
Helen
H
Shipley
Steven T
ST
Bartlett
Stephen T
ST
Rodriguez
Eduardo D
ED
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D004195:Disease Models, Animal; D054445:Facial Transplantation / Q000009:adverse effects*; D006084:Graft Rejection / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D007518:Isoantibodies / Q000097:blood; D007959:Lymphocyte Culture Test, Mixed; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D008297:Male; D012307:Risk Factors; D020123:Sirolimus / Q000008:administration & dosage; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D007518:Isoantibodies; D020123:Sirolimus; D016559:Tacrolimus