Haanstra Krista G, Sick Ella A, Ringers Jan, Wubben Jacqueline A M, Kuhn Eva-Maria, 't Hart Bert A, Boon Louis, Jonker Margreet
Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, the Netherlands.
Transplantation. 2006 Nov 15;82(9):1194-201. doi: 10.1097/01.tp.0000235910.47214.67.
Costimulation blockade with antibodies directed against human CD40 and CD86 leads to prolonged kidney allograft survival in rhesus monkeys, but fails to induce permanent graft acceptance. We have tested whether costimulation blockade is more effective after peripheral T-cell ablation with antithymocyte globulin (ATG), with the aim to remove already primed autoreactive cells present in the normal repertoire.
Rhesus monkeys were transplanted with a mismatched kidney allograft. ATG was given around the time of transplantation (day -1 and 0). Costimulation blockade with anti-CD40+anti-CD86 was given at tapering dosages from day -1 to 56. Cyclosporin A (CsA) was given from day 42 onwards and first rejections occurring after day 42 were treated with prednisone.
We observed accelerated rejection in ATG-treated monkeys, compared to animals receiving only costimulation blockade. The accelerated rejection of the kidney allograft occurred despite the application of rejection therapy with steroids and CsA. Three of the five ATG-treated animals were found seropositive for donor-specific alloantibodies. Early biopsies (day 21) from animals treated with ATG and anti-CD40+anti-CD86 show substantially reduced expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and forkhead box P3 (FOXP3) in focal infiltrates as compared to animals treated with only costimulation blockade. Furthermore, we observed the rapid reappearance of CD8 T-cells with a memory phenotype (disappearance of naive CD95/CD11a T-cells) in peripheral blood.
We conclude that (subtotal) T-cell depletion using ATG does not add to costimulation blockade induced kidney allograft survival.
用针对人类CD40和CD86的抗体进行共刺激阻断可延长恒河猴肾移植的存活时间，但无法诱导永久的移植物接受。我们测试了在用抗胸腺细胞球蛋白（ATG）进行外周T细胞消融后，共刺激阻断是否更有效，目的是清除正常库中已致敏的自身反应性细胞。
将恒河猴移植不匹配的肾移植。在移植时（第-1天和第0天）给予ATG。从第-1天至56天以逐渐减少的剂量给予抗CD40 +抗CD86进行共刺激阻断。从第42天起给予环孢素A（CsA），第42天后发生的首次排斥反应用泼尼松治疗。
与仅接受共刺激阻断的动物相比，我们观察到接受ATG治疗的猴子发生加速排斥。尽管应用了类固醇和CsA进行排斥治疗，但肾移植仍发生了加速排斥。在接受ATG治疗的五只动物中，有三只被发现供体特异性同种抗体呈血清阳性。与仅接受共刺激阻断治疗的动物相比，接受ATG和抗CD40 +抗CD86治疗的动物在早期活检（第21天）时，局灶性浸润中细胞毒性T淋巴细胞相关抗原-4（CTLA-4）和叉头框P3（FOXP3）的表达明显降低。此外，我们观察到外周血中具有记忆表型的CD8 T细胞迅速重新出现（幼稚CD95 / CD11a T细胞消失）。
我们得出结论，使用ATG进行（部分）T细胞清除并不能增加共刺激阻断诱导的肾移植存活时间。
