通过转移供体的T细胞克隆来重建异基因骨髓受体针对巨细胞病毒的细胞免疫。

Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor.

作者信息

Walter E A, Greenberg P D, Gilbert M J, Finch R J, Watanabe K S, Thomas E D, Riddell S R

机构信息

Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.

出版信息

N Engl J Med. 1995 Oct 19;333(16):1038-44. doi: 10.1056/NEJM199510193331603.

DOI:10.1056/NEJM199510193331603

PMID:7675046

Abstract

BACKGROUND

Cytomegalovirus (CMV) disease in immunocompromised patients correlates with a deficiency of CD8+ cytotoxic T lymphocytes specific for CMV. We evaluated the safety and immunologic effects of immunotherapy with clones of these lymphocytes in recipients of allogeneic bone marrow transplants.

METHODS

Clones of CD8+ cytotoxic T cells specific for CMV proteins were isolated from the blood of bone marrow donors. Fourteen patients each received four intravenous infusions of these clones from their donors beginning 30 to 40 days after marrow transplantation. The reconstitution of cellular immunity against CMV was monitored before and during the period of infusions and for up to 12 weeks after the final infusion. The rearranged genes encoding the T-cell receptor served as markers in evaluating the persistence of the transferred T cells.

RESULTS

No toxic effects related to the infusions were observed. Cytotoxic T cells specific for CMV were reconstituted in all patients. In vitro measurements showed that cytotoxic activity against CMV was significantly increased (P < 0.001) after the infusions in 11 patients who were deficient in such activity before therapy. The level of activity achieved after the infusions was similar to that measured in the donors. Analysis of rearranged T-cell-receptor genes in T cells obtained from two recipients indicated that the transferred clones persisted for at least 12 weeks. Cytotoxic-T-cell activity declined in patients deficient in CD4+ T-helper cells specific for CMV, suggesting that helper-T-cell function is needed for the persistence of transferred CD8+ T cells. Neither CMV viremia nor CMV disease developed in any of the 14 patients.

CONCLUSIONS

The transfer of CMV-specific clones of CD8+ T cells derived from the bone marrow donor is a safe and effective way to reconstitute cellular immunity against CMV after allogeneic marrow transplantation.

摘要

背景

免疫功能低下患者的巨细胞病毒（CMV）疾病与针对CMV的CD8 + 细胞毒性T淋巴细胞缺乏有关。我们评估了用这些淋巴细胞克隆进行免疫治疗对异基因骨髓移植受者的安全性和免疫效果。

方法

从骨髓供者血液中分离出针对CMV蛋白的CD8 + 细胞毒性T细胞克隆。14例患者在骨髓移植后30至40天开始，各自接受来自其供者的这些克隆的四次静脉输注。在输注期间及输注前和最后一次输注后长达12周监测针对CMV的细胞免疫重建情况。编码T细胞受体的重排基因作为评估转移T细胞持久性的标志物。

结果

未观察到与输注相关的毒性作用。所有患者均重建了针对CMV的细胞毒性T细胞。体外测量显示，11例治疗前缺乏这种活性的患者在输注后针对CMV的细胞毒性活性显著增加（P < 0.001）。输注后达到的活性水平与供者中测得的相似。对两名受者获得的T细胞中重排的T细胞受体基因分析表明，转移的克隆持续至少12周。在缺乏针对CMV的CD4 + 辅助性T细胞的患者中，细胞毒性T细胞活性下降，提示辅助性T细胞功能是转移的CD8 + T细胞持久性所必需的。14例患者中无一例发生CMV病毒血症或CMV疾病。