CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease
CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease
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DOI：
10.1038/sj.leu.2404720
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发表时间：
2007-07-01
期刊：
影响因子：
11.4
通讯作者：
Vandenberghe, P.
中科院分区：
文献类型：
--
作者：
Fevery, S.;Billiau, A. D.;Vandenberghe, P.
我们研究了CTLA-4阻断对小鼠轻微组织相容性不匹配骨髓移植模型中移植物抗白血病和移植物抗宿主反应的影响。早期CTLA-4阻断诱导急性移植物抗宿主病。延迟的CTLA-4阻断导致淋巴脾肿大的致死性条件，但具有稳定的混合T细胞嵌合体，同种异体反应性T细胞频率不变，并且在体外不存在抗宿主反应性。与此相反，多器官淋巴组织增生性疾病与自身免疫性肝炎和循环抗DNA自身抗体的记录。脾淋巴细胞表现出离体自发增殖和显着的增殖反应，对宿主型树突状细胞与同源（宿主型）组织肽脉冲。这两种现象都是由宿主而不是供体T细胞介导的，支持自身免疫发病机制。选择性宿主来源的T细胞免疫反应性同样记录对白血病肽脉冲树突状细胞，这是由一个强大的抗CTLA-4治疗，随后白血病攻击嵌合体体内抗白血病作用。总之，延迟CTLA-4阻断诱导宿主源性抗白血病效应，发生在自身免疫综合征的背景下，并严格与移植物抗宿主病分开。抗白血病和自身免疫反应都依赖于同种异体成分，因为在同基因骨髓移植后没有观察到任何效果。我们的研究结果揭示了在异基因造血干细胞移植后使用CTLA-4阻断剂建立抗白血病效应的潜力，前提是自身免疫可以得到控制。
We studied the effect of CTLA-4 blockade on graft-versus-leukemia and graft-versus-host responses in a mouse model of minor histocompatibility-mismatched bone marrow transplantation. Early CTLA-4 blockade induced acute graft-versus-host disease. Delayed CTLA-4 blockade resulted in a lethal condition with lymphosplenomegaly, but with stable mixed T-cell chimerism, unchanged alloreactive T-cell frequencies and absent anti-host reactivity in vitro. In contrast, multiorgan lymphoproliferative disease with autoimmune hepatitis and circulating anti-DNA auto-antibodies were documented. Splenic lymphocytes exhibited ex vivo spontaneous proliferation and a marked proliferative response against host-type dendritic cells pulsed with syngeneic (host-type) tissue-peptides. Both phenomena were exclusively mediated by host and not donor T cells, supporting an autoimmune pathogenesis. Selectively host-derived T-cell immune reactivity was equally documented against leukemia-peptide-pulsed dendritic cells, and this was paralleled by a strong in vivo antileukemic effect in anti-CTLA-4-treated and subsequently leukemia-challenged chimeras. In conclusion, delayed CTLA-4 blockade induced a host-derived antileukemic effect, occurring in the context of an autoimmune syndrome and strictly separated from graft-versus-host disease. Both antileukemic and autoimmune responses depended on the allogeneic component, as neither effect was seen after syngeneic bone marrow transplantation. Our findings reveal the potential of using CTLA-4 blockade to establish antileukemic effects after allogeneic hematopoietic stem cell transplantation, provided autoimmunity can be controlled.