Department of Hematology, Leiden University Medical Center, Leiden, Netherlands.
Center for Clinical Transfusion Research, Sanquin Research, Leiden, Netherlands.
Front Immunol. 2018 Dec 18;9:3016. doi: 10.3389/fimmu.2018.03016. eCollection 2018.
Under non-inflammatory conditions HLA class II is predominantly expressed on hematopoietic cells. Therefore, donor CD4 T-cells after allogeneic stem cell transplantation (alloSCT) may mediate graft-vs.-leukemia reactivity without graft-vs.-host disease (GVHD). We analyzed immune responses in four patients converting from mixed to full donor chimerism without developing GVHD upon purified CD4 donor lymphocyte infusion (DLI) from their HLA-identical sibling donor after T-cell depleted alloSCT. activated T-cells were clonally isolated after CD4 DLI. Of the alloreactive T-cell clones, 96% were CD4 positive, illustrating the dominant role of CD4 T-cells in the immune responses. We identified 9 minor histocompatibility antigens (MiHA) as targets for alloreactivity, of which 8 were novel HLA class II restricted MiHA. In all patients, MiHA specific CD4 T-cells were found that were capable to lyse hematopoietic cells and to recognize normal and malignant cells. No GVHD was induced in these patients. Skin fibroblasts forced to express HLA class II, were recognized by only two MiHA specific CD4 T-cell clones. Of the 7 clones that failed to recognize fibroblasts, two targeted MiHA were encoded by genes not expressed in fibroblasts, presentation of one MiHA was dependent on HLA-DO, which is absent in fibroblasts, and T-cells recognizing the remaining 4 MiHA had an avidity that was apparently too low to recognize fibroblasts, despite clear recognition of hematopoietic cells. In conclusion, purified CD4 DLI from HLA-identical sibling donors can induce conversion from mixed to full donor chimerism with graft-vs.-malignancy reactivity, but without GVHD, by targeting HLA class II restricted MiHA.
在非炎症条件下，HLA Ⅱ类主要在造血细胞上表达。因此，异基因造血干细胞移植（alloSCT）后供体 CD4 T 细胞可能介导移植物抗白血病反应而不发生移植物抗宿主病（GVHD）。我们分析了 4 例患者在 T 细胞耗竭 alloSCT 后接受 HLA 同基因供体来源的纯化 CD4 供体淋巴细胞输注（DLI）从混合嵌合状态转为完全供体嵌合状态且无 GVHD 发生时的免疫反应。CD4 DLI 后，对激活的 T 细胞进行克隆分离。在同种反应性 T 细胞克隆中，96%为 CD4 阳性，表明 CD4 T 细胞在免疫反应中起主导作用。我们鉴定了 9 个次要组织相容性抗原（MiHA）作为同种反应性的靶标，其中 8 个是新的 HLA Ⅱ类限制的 MiHA。在所有患者中，均发现 MiHA 特异性 CD4 T 细胞能够裂解造血细胞并识别正常和恶性细胞。这些患者未发生 GVHD。表达 HLA Ⅱ类的皮肤成纤维细胞仅被两个 MiHA 特异性 CD4 T 细胞克隆识别。在未能识别成纤维细胞的 7 个克隆中，有两个靶向 MiHA 的基因不在成纤维细胞中表达，一个 MiHA 的呈递依赖于成纤维细胞中不存在的 HLA-DO，而识别其余 4 个 MiHA 的 T 细胞的亲和力显然太低，无法识别成纤维细胞，尽管它们明显可以识别造血细胞。总之，来自 HLA 同基因供体的纯化 CD4 DLI 可以通过靶向 HLA Ⅱ类限制的 MiHA 诱导从混合嵌合状态转为完全供体嵌合状态，从而具有移植物抗恶性肿瘤反应，但无 GVHD。
