Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany.
Eur J Immunol. 2018 Dec;48(12):2055-2067. doi: 10.1002/eji.201847669. Epub 2018 Nov 14.
Donor lymphocyte infusions together with allogeneic hematopoietic stem cell transplantation are routinely used as second-line treatment for hematological malignancies. Mature T cells in the graft crucially mediate a graft versus leukemia (GvL) response, but also attack healthy tissues in the recipient leading to potentially life-threatening acute graft versus host disease. Using inducible CD28 knockout C57BL/6 mice as T-cell donors, we have now assessed whether CD28 costimulation of donor CD4 and/ or CD8 T cells is required for an efficient GvL effect after allogeneic T-cell transplantation into BALB/c recipients. Our results show that CD28 costimulation of donor CD8 cytotoxic, but not CD4 helper, T cells was dispensable for curing mice from the BCL-1 lymphoma. Therefore, donor lymphocyte infusion treated lymphoma-bearing BALB/c recipient mice showed enhanced long-term survival when receiving CD28-deficient as compared to wild-type donor CD8 T cells together with wild-type conventional and regulatory CD4 T cells. The same was observed when donor CD8 and conventional and regulatory CD4 T cells were CD28 deficient. Our data, thus, suggest that systemic CD28 blockade, for example, with the drug FR104 might also reduce acute graft versus host disease in patients after allogeneic hematopoietic stem cell transplantation, while maintaining the protective GvL response.
供者淋巴细胞输注联合异基因造血干细胞移植通常被用作血液系统恶性肿瘤的二线治疗方法。移植物中的成熟 T 细胞在移植物抗白血病（GVL）反应中起关键作用，但也会攻击受者体内的健康组织，导致潜在危及生命的急性移植物抗宿主病（GVHD）。本研究使用诱导型 CD28 敲除 C57BL/6 小鼠作为 T 细胞供者，评估了在同种异体 T 细胞移植到 BALB/c 受者后，供者 CD4 和/或 CD8 T 细胞的 CD28 共刺激是否需要有效发挥 GVL 效应。结果表明，CD28 共刺激供者 CD8 细胞毒性 T 细胞而非 CD4 辅助性 T 细胞对于治愈 BCL-1 淋巴瘤小鼠是可有可无的。因此，与输注野生型供者 CD8 T 细胞相比，接受 CD28 缺陷型供者 CD8 T 细胞以及野生型常规和调节性 CD4 T 细胞输注的淋巴瘤荷瘤 BALB/c 受者小鼠显示出增强的长期存活。当供者 CD8 和常规及调节性 CD4 T 细胞均缺乏 CD28 时，也观察到了同样的现象。因此，我们的数据表明，全身 CD28 阻断，例如使用药物 FR104，在同种异体造血干细胞移植后也可能减轻患者的急性 GVHD，同时维持保护性 GVL 反应。
