title: Simultaneous transplantation of hematopoietic stem cells and a vascularized composite allograft leads to tolerance.
abstract: BACKGROUND
  We have previously demonstrated that tolerance to a vascularized composite allograft (VCA) can be achieved after the establishment of mixed chimerism. We test the hypothesis that tolerance to a VCA in our dog leukocyte antigen-matched canine model is not dependent on the previous establishment of mixed chimerism and can be induced coincident with hematopoietic cell transplantation (HCT).
  
  
  METHODS
  Eight dog leukocyte antigen-matched, minor antigen mismatched dogs received 200 cGy of radiation and a VCA transplant. Four dogs received donor bone marrow at the time of VCA transplantation (group 1), whereas a second group of four dogs did not (group 2). All recipients received a limited course of postgrafting immunosuppression. All dogs that received HCT and VCA were given donor, third-party, and autologous skin grafts.
  
  
  RESULTS
  All group 1 recipients were tolerant to their VCA (>62 weeks). Three of the four dogs in group 2 rejected their VCA transplants after the cessation of immunosuppression. Biopsies obtained from the muscle and skin of VCA from group 1 showed few infiltrating cells compared with extensive infiltrates in biopsies of VCA from group 2. Compared with autologous skin and muscle, elevated levels of CD3+ FoxP3+ T-regulatory cells were found in the skin and muscle obtained from the VCA of HCT recipients. All group 1 animals were tolerant to their donor skin graft and promptly rejected the third-party skin grafts.
  
  
  CONCLUSIONS
  These data demonstrated that donor-specific tolerance to all components of the VCA can be established through simultaneous nonmyeloablative allogeneic HCT and VCA transplantation protocol.
authors.affiliation: 1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. 2 Department of Surgery, University of Washington, Seattle, WA. 3 Plastic Surgery Service, VA Puget Sound Health Care System, Seattle, WA. 4 Department of Medicine, University of Washington, Seattle, WA. 5 School of Public Health, University of Washington, Seattle, WA. 6 Department of Pathology, University of Washington, Seattle, WA. 7 Address correspondence to: David W. Mathes, M.D., Clinical Research Division, Fred Hutchinson Cancer Research Center, PO Box 19024; D1-100 1100 Fairview Ave, N, Seattle, WA 98109.
authors.forename: David W
authors.initials: DW
authors.lastname: Mathes
authors.forename: Jeff
authors.initials: J
authors.lastname: Chang
authors.forename: Billanna
authors.initials: B
authors.lastname: Hwang
authors.forename: Scott S
authors.initials: SS
authors.lastname: Graves
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: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D064595:Composite Tissue Allografts; D016207:Cytokines / Q000378:metabolism; D004285:Dogs; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006648:Histocompatibility; D006649:Histocompatibility Antigens / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019653:Myeloablative Agonists / Q000494:pharmacology; D016038:Skin Transplantation / Q000009:adverse effects; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D018183:Transplantation Chimera; D023001:Transplantation Tolerance / Q000187:drug effects; D063986:Vascularized Composite Allotransplantation / Q000009:adverse effects
chemical_list: D015415:Biomarkers; D017252:CD3 Complex; D016207:Cytokines; D051858:Forkhead Transcription Factors; D006649:Histocompatibility Antigens; D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists