Donor-specific tolerance in fully major histocompatibility major histocompatibility complexmismatched limb allograft transplants under an anti-&agr;&bgr; T-cell receptor monoclonal antibody and cyclosporine A protocol
作者:
Maria Siemionow,
Dariusz Izycki,
Maciej Zielinski,
期刊:
Transplantation
(OVID Available online 2003)
卷期:
Volume 76,
issue 12
页码: 1662-1668
ISSN:0041-1337
年代: 2003
出版商: OVID
数据来源: OVID
摘要:
Background.Recent studies have demonstrated that treatment with &agr;&bgr;–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 &agr;&bgr;-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 &agr;&bgr;-TCR and CsA or a combination of &agr;&bgr;-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 &agr;&bgr;-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 (A×C 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 &agr;&bgr;-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.
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