title: Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model.
abstract: BACKGROUND
  We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation "simultaneously."
  
  
  METHODS
  Group 1 included controls in which naïve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI-->WF) chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100 x 10(6) ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy.
  
  
  RESULTS
  The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (>80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity.
  
  
  CONCLUSIONS
  This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.
authors.affiliation: Division of Plastic and Reconstructive Surgery, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Kaustubha A
authors.initials: KA
authors.lastname: Prabhune
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Gorantla
authors.forename: Gustavo
authors.initials: G
authors.lastname: Perez-Abadia
authors.forename: Cedric G
authors.initials: CG
authors.lastname: Francois
authors.forename: Marieke
authors.initials: M
authors.lastname: Vossen
authors.forename: Luis A
authors.initials: LA
authors.lastname: Laurentin-Perez
authors.forename: Warren C
authors.initials: WC
authors.lastname: Breidenbach
authors.forename: Gordon G
authors.initials: GG
authors.lastname: Wang
authors.forename: Gary L
authors.initials: GL
authors.lastname: Anderson
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Pidwell
authors.forename: John H
authors.initials: JH
authors.lastname: Barker
authors.forename: Claudio
authors.initials: C
authors.lastname: Maldonado
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006085:Graft Survival; D006614:Hindlimb / Q000473:pathology / Q000637:transplantation*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008212:Lymphocyte Depletion; D008285:Major Histocompatibility Complex; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D011912:Rats, Inbred ACI; D011920:Rats, Inbred WF; D013601:T-Lymphocytes / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous / Q000276:immunology* / Q000473:pathology; D014916:Whole-Body Irradiation
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid