Induction of tolerance in composite-tissue allografts.
BACKGROUND
Transplantation of composite-tissue allograft (CTA) such as the human hand recently became a clinical reality. The high risks associated with the use of lifelong immunosuppression have been the prohibiting factor in the routine use of the CTA transplants. In this article, we present a new approach of inducing long-term, donor-specific tolerance to CTAs without recipient preconditioning and need for chronic immunosuppression.


METHODS
We have developed a clinically applicable 35-day protocol that induces donor-specific tolerance in a rat hindlimb-transplantation model across major histocompatibility complex (MHC) barrier [Lewis-Brown-Norway (LBN, RT1 -->F1) to Lewis (LEW, RT1 ) by using cyclosporine A (CsA) and a mouse monoclonal antibody against rat alphabeta-T-cell receptor (TCR) to systemically eliminate alloresponsive cells. Standard skin grafting, flow cytometry (FC), and mixed lymphocyte reaction (MLR) were used to assess efficacy of immunodepletion and confirm donor-specific tolerance and chimerism.


RESULTS
Under this protocol long-term tolerance (>720 days) was induced in all (n=5) CTA recipients across the MHC barrier without further need for immunosuppression. Tolerance was confirmed in all limb-allograft recipients by skin grafting in vivo and by MLR in vitro. The animals rejected third-party grafts, indicating immunocompetence.


CONCLUSIONS
In this CTA model, combined protocol of alphabeta-TCR monoclonal antibody and CsA resulted in induction of donor-specific tolerance across the MHC barrier without recipient conditioning. We believe that our findings will foster development of new therapeutic strategies and expand clinical applications for composite-tissue transplantation.
Siemionow
Maria
M
Department of Plastic Surgery, Microsurgery Laboratory, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. siemiom@ccf.org.
Ortak
Turgut
T
Izycki
Dariusz
D
Oke
Ramadan
R
Cunningham
Brian
B
Prajapati
Rita
R
Zins
James E
JE
D000818:Animals; D002199:Capillary Permeability; D002678:Chimera; D005434:Flow Cytometry; D006085:Graft Survival; D006439:Hemodynamics; D006614:Hindlimb / Q000098:blood supply / Q000637:transplantation*; D007121:Immunocompetence; D007165:Immunosuppression Therapy; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008833:Microcirculation; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020127:Recovery of Function; D016038:Skin Transplantation; D014019:Tissue Donors; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous