title: Prolonged survival of composite facial allografts in non-human primates associated with posttransplant lymphoproliferative disorder.
abstract: 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.
authors.affiliation: Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD, USA. rbarth@smail.umaryland.edu
authors.forename: Rolf N
authors.initials: RN
authors.lastname: Barth
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Nam
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Stanwix
authors.forename: Debra
authors.initials: D
authors.lastname: Kukuruga
authors.forename: Cinthia I
authors.initials: CI
authors.lastname: Drachenberg
authors.forename: Rachel
authors.initials: R
authors.lastname: Bluebond-Langner
authors.forename: Helen
authors.initials: H
authors.lastname: Hui-Chou
authors.forename: Steven T
authors.initials: ST
authors.lastname: Shipley
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Bartlett
authors.forename: Eduardo D
authors.initials: ED
authors.lastname: Rodriguez
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D007518:Isoantibodies; D020123:Sirolimus; D016559:Tacrolimus