Boulday Gwénola, Ashton-Chess Joanna, Bernard Pierre, Karam Georges, Vié Henri, Moreau Anne, Minault David, Lorré Katrien, Soulillou Jean-Paul, Blancho Gilles
INSERM U437, Immunointervention en Allo et Xénotransplantation, Nantes cedex, France.
Nephrol Dial Transplant. 2004 Jul;19(7):1752-60. doi: 10.1093/ndt/gfh126. Epub 2004 Apr 6.
Co-stimulation blockade has already been shown to induce transplantation tolerance in rodents, but until now has failed in large animal models. We therefore sought to investigate whether the addition of rapamycin to a co-stimulation blockade regimen could induce tolerance in baboon recipients of a renal allograft and to characterize the immunological characteristics of rejection.
Two baboons were used for a pharmacological and toxicological analysis and received anti-B7.1 and anti-B7 antibodies every other day for 60 days. Three groups of baboons underwent classical heterotopic renal allotransplantation; the first group received no treatment (control group; n = 2), the second received a combination of anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) (B7 group; n = 4), and the third received the anti-B7 antibody treatment as above with an additional treatment of rapamycin (B7-Rapa; n = 4). Graft survival as well as immunological analyses were performed.
Anti-B7 mAb monotherapy prolonged allograft survival in three out of four of the animals, one of whom survived rejection free for 87 days but died from a pulmonary embolism; the fourth animal died without rejection. The addition of rapamycin to the regimen did not prolong survival further; three of the four animals underwent early rejection whereas the fourth survived long term but eventually rejected at day 114. Whereas alloimmunization only occurred in this latter animal, rejection was always characterized by a substantial lymphocyte and monocyte infiltration, associated with a strong pro-inflammatory/cytotoxic mRNA accumulation in the anti-B7-treated animals, but to a lesser extent in the B7-Rapa group. T cells extracted and cloned from a biopsy taken at a stable post-transplant time showed a lower frequency of anti-donor alloreactivity in vitro than those extracted from a rejected tissue. Nevertheless, these non-responding clones failed to show regulatory activity in vitro.
We thus confirm that blocking the CD28/B7 pathway by anti-B7 mAbs could prolong graft survival in baboons, but the addition of rapamycin was insufficient to induce tolerance.
共刺激阻断已被证明可在啮齿动物中诱导移植耐受，但迄今为止在大型动物模型中尚未成功。因此，我们试图研究在共刺激阻断方案中添加雷帕霉素是否能诱导肾移植狒狒受体产生耐受，并确定排斥反应的免疫特征。
使用两只狒狒进行药理学和毒理学分析，每隔一天接受抗B7.1和抗B7抗体治疗，持续60天。三组狒狒接受经典的异位肾同种异体移植；第一组不接受治疗（对照组；n = 2），第二组接受抗CD80和抗CD86单克隆抗体（mAb）联合治疗（B7组；n = 4），第三组接受上述抗B7抗体治疗并额外接受雷帕霉素治疗（B7-Rapa组；n = 4）。进行移植物存活以及免疫分析。
抗B7 mAb单一疗法使四只动物中的三只移植物存活期延长，其中一只无排斥存活87天，但死于肺栓塞；第四只动物未发生排斥反应而死亡。在方案中添加雷帕霉素并未进一步延长存活期；四只动物中的三只发生早期排斥反应，而第四只长期存活但最终在第114天发生排斥反应。虽然同种免疫仅发生在这只后期动物中，但排斥反应总是以大量淋巴细胞和单核细胞浸润为特征，在抗B7治疗的动物中伴有强烈的促炎/细胞毒性mRNA积累，但在B7-Rapa组中程度较轻。在移植后稳定期活检中提取并克隆的T细胞在体外显示出比从排斥组织中提取的T细胞更低频率的抗供体同种异体反应性。然而，这些无反应性克隆在体外未能显示出调节活性。
因此，我们证实通过抗B7 mAb阻断CD28/B7途径可延长狒狒的移植物存活期，但添加雷帕霉素不足以诱导耐受。
