Donor-specific tolerance in fully major histocompatibility major histocompatibility complex-mismatched limb allograft transplants under an anti-alphabeta T-cell receptor monoclonal antibody and cyclosporine A protocol

Transplantation. 2003 Dec 27;76(12):1662-8. doi: 10.1097/01.TP.0000105343.49626.6F.

Abstract

Background: Recent studies have demonstrated that treatment with alphabeta-T-cell receptor (TCR) monoclonal antibody and cyclosporine A (CsA) can extend survival in composite tissue allografts (CTA). The purpose of this study was to induce tolerance in fully major histocompatibility complex (MHC)-mismatched rat limb allografts under 7 days of a combined alphabeta-TCR-CsA protocol.

Methods: The authors performed 30 hind-limb allotransplantations across the MHC barrier between Brown Norway donors (BN; RT1n) and Lewis recipients (LEW; RT1l). Isograft and allograft controls received no treatment. The experimental groups received monotherapy of alphabeta-TCR and CsA or a combination of alphabeta-TCR and CsA for 7 days only. Donor-specific tolerance and immunocompetence were determined by standard skin grafting in vivo and mixed lymphocyte reaction (MLR) in vitro. The efficacy of immunosuppressive therapy and the level of donor-specific chimerism were determined by flow cytometry.

Results: Long-term survival (>350 days) was achieved in allograft recipients (n=6) under the 7-day protocol of combined alphabeta-TCR-CsA. Donor-specific tolerance and immunocompetence of long-term chimeras were confirmed by acceptance of skin grafts from the donors and rejection of the third-party alloantigens (AxC Irish). At day 120, MLR demonstrated unresponsiveness to the host and donor antigens but strong reactivity against third-party alloantigens. Flow cytometry confirmed the high efficacy of immunosuppressive treatment and the development of donor-specific chimerism (7.6% of CD4+-RT1n+ cells, 1.3% of CD8+-RT1n+ cells, and 16.5% of CD45RA+-RT1n+ cells) in the periphery of tolerated recipients.

Conclusions: Combined therapy of alphabeta-TCR-CsA for 7 days resulted in tolerance induction in fully MHC-mismatched rat hind-limb allografts. Tolerance was directly associated with stable, donor-specific chimerism.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Cyclosporine / therapeutic use*
  • Flow Cytometry
  • Graft Survival / drug effects
  • Graft Survival / immunology*
  • Hindlimb / transplantation*
  • Histocompatibility Testing
  • Immunosuppressive Agents / therapeutic use*
  • Lymphocyte Depletion
  • Major Histocompatibility Complex*
  • Models, Animal
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred Lew
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • Time Factors
  • Transplantation, Homologous / immunology*
  • Transplantation, Homologous / pathology

Substances

  • Antibodies, Monoclonal
  • Immunosuppressive Agents
  • Receptors, Antigen, T-Cell, alpha-beta
  • Cyclosporine