title: Tolerance to vascularized composite allografts in canine mixed hematopoietic chimeras.
abstract: BACKGROUND
  Mixed donor-host chimerism, established through hematopoietic cell transplantation (HCT), is a reproducible strategy for the induction of tolerance toward solid organs. Here, we ask whether a nonmyeloablative conditioning regimen establishing mixed donor-host chimerism leads to tolerance of antigenic vascularized composite allografts.
  
  
  METHODS
  Stable mixed chimerism was established in dogs given a sublethal dose (1-2 Gy) total body irradiation before and a short course of immunosuppression after dog leukocyte antigen-identical marrow transplantation. Vascularized composite allografts from marrow donors were performed after a median of 36 months (range, 4-54 months) after HCT.
  
  
  RESULTS
  All marrow recipients maintained mixed donor-host hematopoietic chimerism and accepted vascularized composite allografts for periods ranging between 52 and 90 weeks; in turn, marrow donors rejected vascularized composite allografts from their respective marrow recipients within 18 to 29 days. Biopsies of muscle and skin of vascularized composite allografts from mixed chimeras showed few infiltrating cells compared with extensive infiltrates in biopsies of vascularized composite allografts from marrow donors. Elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle of vascularized composite allografts of mixed chimeras compared with normal tissues. In mixed chimeras, increased numbers of T-regulatory cells were found in draining compared with nondraining lymph nodes of vascularized composite allografts.
  
  
  CONCLUSIONS
  These data suggest that nonmyeloablative HCT may form the basis for future clinical applications of solid organ transplantation and that T-regulatory cells may function toward maintenance of the vascularized composite allograft.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. dmathes@fhcrc.org
authors.forename: David W
authors.initials: DW
authors.lastname: Mathes
authors.forename: Billanna
authors.initials: B
authors.lastname: Hwang
authors.forename: Scott S
authors.initials: SS
authors.lastname: Graves
authors.forename: James
authors.initials: J
authors.lastname: Edwards
authors.forename: Jeff
authors.initials: J
authors.lastname: Chang
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.forename: Tiffany
authors.initials: T
authors.lastname: Butts-Miwongtum
authors.forename: George E
authors.initials: GE
authors.lastname: Sale
authors.forename: Richard A
authors.initials: RA
authors.lastname: Nash
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002678:Chimera; D004285:Dogs; D006084:Graft Rejection / Q000276:immunology; D007108:Immune Tolerance; D018919:Neovascularization, Physiologic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
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