Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Cancer Immunol Immunother. 2012 Jul;61(7):1125-36. doi: 10.1007/s00262-011-1187-z. Epub 2011 Dec 24.
PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30-120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compared with 2/5 BCR-ABL-positive patients (P = 0.025). In contrast, PR1 responses were detected in 2/4 MRD-negative compared with 4/5 MRD-positive ALL patients (P = 0.76). To assess whether the lymphopenic milieu also exaggerates weak T-cell responses in the autologous setting, we measured spontaneous induction of PR1 responses in 3 AML patients vaccinated with WT1-126 peptide following lymphodepletion. In addition to WT1-specific T cells, we detected PR1-specific T cells in 2 patients during hematopoietic recovery. Our findings suggest that lymphopenia induced by chemo-radiotherapy enhances weak autoimmune responses to self-antigens, which may result in GVL if the leukemia expresses the relevant self-antigen.
PR1 是蛋白酶-3（PR3）和弹性蛋白酶（ELA2）蛋白共享的 HLA-A*0201 表位，在正常中性粒细胞中表达，并在髓系白血病中过度表达。PR1 特异性 T 细胞与移植物抗白血病（GVL）效应有关。我们假设化疗和放疗引起的淋巴细胞减少症可以增强对自身抗原（如 PR1）的弱自身免疫反应。我们在异基因干细胞移植（SCT）后 30-120 天测量了 27 例患者的 PR1 特异性反应，并将这些反应与 ELA2 和 PR3 表达及微小残留病（MRD）相关联。在 SCT 后，10/13 例 CML、6/9 例 ALL 和 4/5 例实体瘤患者的 PR1 反应与 PR3 和 ELA2 表达相关。在 SCT 后 180 天，8/8 例有 PR1 反应的 CML 患者 BCR-ABL 阴性，而 5/5 例 BCR-ABL 阳性患者中仅有 2 例（P = 0.025）。相比之下，在 4/5 例 ALL 患者 MRD 阳性中检测到 PR1 反应，而在 2/4 例 MRD 阴性患者中检测到 PR1 反应（P = 0.76）。为了评估淋巴细胞减少症是否也会夸大自身环境中的弱 T 细胞反应，我们在 3 例接受 WT1-126 肽淋巴耗竭疫苗接种的 AML 患者中测量了 PR1 反应的自发诱导。除了 WT1 特异性 T 细胞外，我们在 2 例患者造血恢复期间还检测到了 PR1 特异性 T 细胞。我们的研究结果表明，化疗和放疗引起的淋巴细胞减少症增强了对自身抗原的弱自身免疫反应，如果白血病表达相关的自身抗原，则可能导致 GVL。
