巨细胞病毒特异性 T 细胞免疫疗法促进异基因干细胞移植后持久的功能性抗病毒免疫恢复。

Cytomegalovirus-specific T cell immunotherapy promotes restoration of durable functional antiviral immunity following allogeneic stem cell transplantation.

机构信息

Department of Haematology, UCL Medical School, University College London, London, United Kingdom.

出版信息

Clin Infect Dis. 2009 Dec 15;49(12):1851-60. doi: 10.1086/648422.

DOI:10.1086/648422

PMID:19911966

Abstract

BACKGROUND

The profound immunodeficiency associated with allogeneic hematopoietic stem cell transplantation is permissive to uncontrolled replication of latent human herpesviridae such as cytomegalovirus. Morbidity and mortality associated with viral dissemination or its treatment are significant. Although adoptive cellular therapy with virus-specific T cells offers the potential for accelerating pathogen-specific immune reconstitution, the risk of induction of graft-versus-host disease and the logistics of production of clonal T cell populations restrict application.

METHODS

We investigated the ability of cytomegalovirus-specific mixed CD4(+) and CD8(+) T cell lines, generated by short-term ex vivo culture of donor lymphocytes with donor monocyte-derived dendritic cells pulsed with virus lysate, to restore antiviral immunity in 30 allogeneic transplant recipients at high risk of both uncontrolled viral replication and of graft-versus-host disease.

RESULTS

There were no immediate toxicities and no excess of graft-versus-host disease. Massive in vivo expansions of cytomegalovirus-specific T lymphocytes occurred, temporally associating with periods of viral replication, suggesting that antigen exposure was necessary for optimal cytomegalovirus-specific immune reconstitution. The expanding populations maintained functional competence in ex vivo re-stimulation assays, promoting reconstitution of durable functional cytomegalovirus-specific immunity and effectively preventing recurrent viral infection and late cytomegalovirus disease.

CONCLUSIONS

These data confirm the ability of cellular immunotherapy to hasten reconstitution of antiviral immunity following allogeneic transplantation, indicating that significant clinical benefits may be conferred in terms of reduction of secondary viral infection episodes, potentially reducing exposure to the toxicities of antiviral drugs.

摘要

背景

异基因造血干细胞移植所导致的严重免疫缺陷，使潜伏的人类疱疹病毒（如巨细胞病毒）得以不受控制地复制。病毒传播或其治疗相关的发病率和死亡率是显著的。虽然过继细胞疗法用病毒特异性 T 细胞具有加速病原体特异性免疫重建的潜力，但移植物抗宿主病的诱导风险和克隆 T 细胞群体的生产物流限制了其应用。

方法

我们研究了通过用病毒裂解物脉冲处理供体单核细胞衍生的树突状细胞来体外短期培养供体淋巴细胞产生的巨细胞病毒特异性混合 CD4(+)和 CD8(+)T 细胞系，在 30 名高风险的异基因移植受者中恢复抗病毒免疫的能力，这些受者存在不受控制的病毒复制和移植物抗宿主病的风险。

结果

没有立即出现毒性，也没有发生过多的移植物抗宿主病。巨细胞病毒特异性 T 淋巴细胞发生了大规模的体内扩增，与病毒复制期相关，表明抗原暴露对于最佳的巨细胞病毒特异性免疫重建是必要的。扩增的群体在体外再刺激试验中保持了功能能力，促进了持久的功能性巨细胞病毒特异性免疫重建，并有效地防止了复发性病毒感染和晚期巨细胞病毒疾病。