Blaha Peter, Bigenzahn Sinda, Koporc Zvonimir, Schmid Maximilian, Langer Felix, Selzer Edgar, Bergmeister Helga, Wrba Friedrich, Kurtz Josef, Kiss Christopher, Roth Erich, Muehlbacher Ferdinand, Sykes Megan, Wekerle Thomas
Division of Transplantation, Department of Surgery, Vienna General Hospital, University of Vienna, Austria.
Blood. 2003 Apr 1;101(7):2886-93. doi: 10.1182/blood-2002-10-3014. Epub 2002 Nov 14.
We recently developed a murine protocol for the induction of allogeneic mixed chimerism and tolerance employing nonmyeloablative total body irradiation (TBI), standard-dose bone marrow transplantation (BMT), and costimulation blockade (cobl) with an anti-CD154 monoclonal antibody (mAb) plus CTLA4Ig. We now evaluated whether a short course (1 month) of immunosuppressive drugs, which would be ethically required in the clinical setting of organ transplantation to prevent graft loss in case tolerance is not achieved, interferes with tolerance induced with this regimen. Our results show that calcineurin inhibitors (cyclosporin A [CyA] or tacrolimus [FK]) inhibit development of long-term chimerism and abrogate tolerance induction in this model. Rapamycin (rapa), methylprednisolone (MP), FTY720, and mycophenolate mofetil (MMF), in contrast, have no negative effect on chimerism or tolerance development. Peripheral deletion of donor-reactive T cells, which usually occurs in the weeks following BMT in this model, is blocked by CyA and FK, but not by the other drugs tested. Furthermore, we found that the additional use of compatible immunosuppressive drugs (rapa plus MMF plus MP) allows the dose of TBI to be reduced, so that mixed chimerism and donor skin-graft acceptance can be achieved with 1 Gy using clinically feasible cell numbers. Thus, this protocol of BMT with costimulation blockade can be safely combined with a clinically tested immunosuppressive regimen to permit success with a lower dose of irradiation. These results should facilitate clinical application of this tolerance strategy.
我们最近开发了一种小鼠方案，用于诱导同种异体混合嵌合体和耐受性，该方案采用非清髓性全身照射（TBI）、标准剂量骨髓移植（BMT）以及用抗CD154单克隆抗体（mAb）加CTLA4Ig进行共刺激阻断（cobl）。我们现在评估了在器官移植临床环境中，若未实现耐受性则为防止移植物丢失而按伦理要求使用的短期（1个月）免疫抑制药物，是否会干扰该方案诱导的耐受性。我们的结果表明，钙调神经磷酸酶抑制剂（环孢素A [CyA] 或他克莫司 [FK]）会抑制该模型中长期嵌合体的形成并消除耐受性诱导。相比之下，雷帕霉素（rapa）、甲泼尼龙（MP）、FTY720和霉酚酸酯（MMF）对嵌合体形成或耐受性发展没有负面影响。在该模型中，通常在BMT后数周发生的供体反应性T细胞的外周缺失被CyA和FK阻断，但未被所测试的其他药物阻断。此外，我们发现额外使用相容性免疫抑制药物（rapa加MMF加MP）可降低TBI剂量，从而使用临床可行的细胞数量，以1 Gy就能实现混合嵌合体和供体皮肤移植接受。因此，这种具有共刺激阻断的BMT方案可安全地与经过临床测试的免疫抑制方案相结合，以较低剂量的照射取得成功。这些结果应有助于这种耐受性策略的临床应用。
