Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, Washington , USA.
Cytotherapy. 2011 Nov;13(10):1269-80. doi: 10.3109/14653249.2011.586997. Epub 2011 Aug 17.
BACKGROUND AIMS. Previously, cytotoxic T lymphocyte antigen 4 (CTLA4) immunoglobulin (Ig) has been shown to allow sustained engraftment in dog leukocyte antigen (DLA)-identical hematopoietic cell transplant (HCT) after non-myeloablative conditioning with 100 cGy total body irradiation (TBI). In the current study, we investigated the efficacy of pre-transplant CTLA4-Ig in promoting engraftment across a DLA-mismatched barrier after non-myeloablative conditioning. METHODS. Eight dogs were treated with CTLA4-Ig and donor peripheral blood mononuclear cells (PBMC) prior to receiving 200 cGy TBI followed by transplantation of granulocyte-colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells from DLA haplo-identical littermates with post-grafting immunosuppression. A control group of six dogs was conditioned with 200 cGy only and transplanted with grafts from DLA haplo-identical littermates followed by post-grafting immunosuppression. RESULTS. In vitro and in vivo donor-specific hyporesponsiveness was demonstrated on day 0 before TBI in eight dogs that received CTLA4-Ig combined with donor PBMC infusions. Four of five dogs treated with increased doses of CTLA4-Ig achieved initial engraftment but eventually rejected, with a duration of mixed chimerism ranging from 12 to 22 weeks. CTLA4-Ig did not show any effect on host natural killer (NK) cell function in vitro or in vivo. No graft-versus-host disease (GvHD) was observed in dogs receiving CTLA4-Ig treatment. CONCLUSIONS. Non-myeloablative conditioning with 200 cGy TBI and CTLA4-Ig combined with donor PBMC infusion was able to overcome the T-cell barrier to achieve initial engraftment without GvHD in dogs receiving DLA haplo-identical grafts. However, rejection eventually occurred; we hypothesize because of the inability of CTLA4-Ig to abate natural killer cell function.
先前的研究表明，细胞毒性 T 淋巴细胞抗原 4（CTLA4）免疫球蛋白（Ig）可在接受 100cGy 全身照射（TBI）的非清髓性预处理后，允许在狗白细胞抗原（DLA）-相同的造血细胞移植（HCT）中持续植入。在目前的研究中，我们研究了在非清髓性预处理后，移植前 CTLA4-Ig 在跨越 DLA 错配屏障促进植入方面的功效。
在接受 200cGy TBI 后，8 只狗接受 CTLA4-Ig 和供体外周血单个核细胞（PBMC）治疗，然后接受来自 DLA 半相合同窝的粒细胞集落刺激因子（G-CSF）动员外周血干细胞移植，并进行移植后免疫抑制。对照组 6 只狗仅接受 200cGy 预处理，并接受来自 DLA 半相合同窝的移植物移植，然后进行移植后免疫抑制。
在接受 CTLA4-Ig 联合供体 PBMC 输注的 8 只狗中，在接受 TBI 前的第 0 天，进行了体外和体内供体特异性低反应性的证明。用增加剂量的 CTLA4-Ig 治疗的 5 只狗中的 4 只狗实现了初始植入，但最终排斥，混合嵌合体持续时间为 12 至 22 周。CTLA4-Ig 对体外和体内宿主自然杀伤（NK）细胞功能均无影响。接受 CTLA4-Ig 治疗的狗未观察到移植物抗宿主病（GvHD）。
200cGy TBI 非清髓性预处理联合 CTLA4-Ig 联合供体 PBMC 输注可克服 T 细胞屏障，在接受 DLA 半相合移植物的狗中实现初始植入而无 GvHD。然而，最终还是发生了排斥；我们假设这是因为 CTLA4-Ig 无法减轻自然杀伤细胞的功能。
