Graft-versus-leukemia antigen CML66 elicits coordinated B-cell and T-cell immunity after donor lymphocyte infusion.
Graft-versus-leukemia antigen CML66 elicits coordinated B-cell and T-cell immunity after donor lymphocyte infusion.
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DOI：
10.1158/1078-0432.ccr-10-0415
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发表时间：
2010-05-15
期刊：
影响因子：
--
通讯作者：
Wu CJ
中科院分区：
文献类型：
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作者：
Zhang W;Choi J;Zeng W;Rogers SA;Alyea EP;Rheinwald JG;Canning CM;Brusic V;Sasada T;Reinherz EL;Ritz J;Soiffer RJ;Wu CJ
与肿瘤相关的移植物抗白血病的靶抗原尚未完全确定。我们检测了针对CML66的反应，CML66是一种免疫原性抗原，在髓系祖细胞中优先表达，来自一名慢性髓系白血病患者，该患者在接受CD4+供者淋巴细胞输注(DLI)后获得长期缓解。从这位患者身上，检测到CML66反应性CD8+T细胞克隆是针对内源性的人类白细胞抗原B*4403限制性表位(HDVDALLW)。DLI前外周血中均未检测到CML66特异性抗体和T细胞反应。然而，在DLI后一个月，外周血中出现CD8+T细胞，骨髓中CD8+T细胞的比例增加了10倍。随后，血浆中抗CML66抗体的产生与疾病缓解有关。供者来源的CML66反应性T细胞在DLI前通过ELISpot和巢式聚合酶链式反应检测克隆型T细胞受体序列在体内检测到低水平，但在DLI前患者和移植供者的血液中不存在。CD4+DLI导致先前存在的常驻白血病特异性供者CD8+T细胞的快速扩增，随后在血液中可检测到一系列抗原特异性免疫反应。因此，我们的单抗原分析表明，移植后持久的肿瘤免疫在一定程度上是针对非多形性过表达的白血病抗原的，这引发了协调的细胞和体液免疫。
The target antigens of graft-versus-leukemia that are tumor-associated are incompletely characterized. We examined responses developing against CML66, an immunogenic antigen preferentially expressed in myeloid progenitor cells identified from a patient with chronic myelogenous leukemia who attained long-lived remission following CD4+ donor lymphocyte infusion (DLI). From this patient, CML66-reactive CD8+ T cell clones were detected against an endogenously presented HLA-B*4403-restricted epitope (HDVDALLW). Neither CML66-specific antibody nor T cell responses were detectable in peripheral blood before DLI. However, by one month after DLI, CD8+ T cells were present in peripheral blood, and at 10-fold higher frequency in marrow. Subsequently, plasma antibody to CML66 developed in association with disease remission. Donor-derived CML66-reactive T cells were detected at low levels in vivo in marrow prior to DLI by ELISpot and by a nested polymerase chain reaction-based assay to detect clonotypic T cell receptor sequences, but not in blood of the patient pre-DLI, nor of the graft donor. CD4+ DLI results in rapid expansion of pre-existing marrow-resident leukemia-specific donor CD8+ T cells, followed by a cascade of antigen-specific immune responses detectable in blood. Our single-antigen analysis thus demonstrates that durable post-transplant tumor immunity is directed in part against nonpolymorphic overexpressed leukemia antigens, that elicit coordinated cellular and humoral immunity.