Induction of tolerance in composite-tissue allografts

• Published in: Transplantation Vol. 74; no. 9; p. 1211
• Main Authors: Siemionow, Maria, Ortak, Turgut, Izycki, Dariusz, Oke, Ramadan, Cunningham, Brian, Prajapati, Rita, Zins, James E
• Format: Journal Article
• Language: English
• Published: United States 15.11.2002
• Subjects: Animals; Capillary Permeability; Chimera; Flow Cytometry; Graft Survival; Hemodynamics; Hindlimb - blood supply; Hindlimb - transplantation; Immunocompetence; Immunosuppression; Lymphocyte Culture Test, Mixed; Male; Microcirculation; Rats; Rats, Inbred BN; Rats, Inbred Lew; Recovery of Function; Skin Transplantation; Tissue Donors; Transplantation Tolerance; Transplantation, Homologous
• ISSN: 0041-1337
• DOI: 10.1097/00007890-200211150-00002

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. 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. 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. 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.