Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model.
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.
Prabhune
Kaustubha A
KA
Division of Plastic and Reconstructive Surgery, University of Louisville, Louisville, Kentucky, USA.
Gorantla
Vijay S
VS
Perez-Abadia
Gustavo
G
Francois
Cedric G
CG
Vossen
Marieke
M
Laurentin-Perez
Luis A
LA
Breidenbach
Warren C
WC
Wang
Gordon G
GG
Anderson
Gary L
GL
Pidwell
Diane J
DJ
Barker
John H
JH
Maldonado
Claudio
C
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
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid