New strategies in allogeneic stem cell transplantation: immunotherapy using irradiated allogeneic T cells.
New strategies in allogeneic stem cell transplantation: immunotherapy using irradiated allogeneic T cells.
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同种异体干细胞移植的新策略：使用辐照同种异体 T 细胞进行免疫治疗。
DOI：
10.1038/sj.bmt.1702347
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Boyer,M
中科院分区：
文献类型：
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作者：
Waller,EK;Boyer,M
T细胞耗尽的同种异体骨髓移植的受者复发和移植物排斥的风险增加。将供体 T 细胞添加到 TCD 同种异体移植物中将降低移植物排斥的风险，但会增加移植物抗宿主病 (GVHD) 的风险。同种异体骨髓移植后白血病或淋巴瘤的复发可以通过移植后输注供体淋巴细胞成功治疗。相对少量的供体 T 细胞可以具有深远的抗肿瘤作用并促进植入，但具有不可预测的严重 GVHD 潜力。使用有活力的免疫活性供体免疫细胞来促进植入和治疗复发患者的另一种选择是供体淋巴细胞，这些细胞经过处理以限制其增殖和引起 GVHD 的能力。经过辐射处理的 T 细胞保留了针对肿瘤细胞和宿主免疫细胞的细胞毒活性。我们已经测试了这样的假设：经过低剂量照射处理的同种异体供体 T 细胞将促进骨髓移植小鼠模型的植入并介导抗白血病作用。在围移植期多次输注经过辐照的同种异体供体淋巴细胞具有移植物增强活性，但不会导致 GVHD。受辐射的同种异体脾细胞和同种异体骨髓的小鼠受体具有稳定的供体来源的造血作用，而受辐射的供体细胞对 T 细胞区室没有显着的贡献。在照射前从同种异体脾细胞中去除 T 细胞很大程度上消除了它们的移植促进活性。基于临床前小鼠研究的有希望的结果，我们启动了一项 I 期临床试验，对同种异体 BMT 后复发的患者多次输注经过辐照的同种异体淋巴细胞。迄今为止，在这项研究中接受治疗的 12 名患者中，有 3 名患者的白血病或淋巴瘤对多次输注经过辐照的供体淋巴细胞显示出客观反应。我们启动了一项新的 I 期临床研究，以测试多次输注经过辐照的同种异体细胞毒性 T 细胞促进同种异体移植中植入的功效。连续的患者队列将被单独移植同种异体干细胞，或异体干细胞和越来越多的经辐照同种异体 T 细胞的组合。经辐照的同种异体淋巴细胞保留了短期同种异体特异性细胞毒性，并且缺乏体内克隆扩增的潜力，可以被认为是一种具有明确药代动力学的新型免疫疗法。骨髓移植（2000）25，增刊。 2、S20-S24。
Recipients of T cell-depleted allogeneic bone marrow transplants have increased risks of relapse and graft rejection. The addition of donor T cells to the TCD allograft will decrease the risk of graft rejection but will increase the risk of graft-versus-host disease (GVHD). Relapse of leukemia or lymphoma following allogeneic bone marrow transplantation can be successfully treated with post-transplant infusions of donor lymphocytes. A relatively small number of donor T cells can have a profound anti-tumor effect and facilitate engraftment, but has an unpredictable potential for severe GVHD. An alternative to using viable immunocompetent donor immune cells to facilitate engraftment and to treat relapsed patients are donor lymphocytes that have been treated to limit their ability to proliferate and cause GVHD. T cells treated with irradiation retain cytotoxic activity against tumor cells and host immune cells. We have tested the hypothesis that allogeneic donor T cells treated with low-dose irradiation will facilitate engraftment and mediate an anti-leukemia effect in a mouse model of bone marrow transplantation. Multiple infusions of irradiated allogeneic donor lymphocytes in the peri-transplant period had graft-enhancing activity without resulting in GVHD. Murine recipients of irradiated allogeneic splenocytes and allogeneic bone marrow had stable donor-derived hematopoiesis without a significant contribution of irradiated donor cells to the T cell compartment. Removing T cells from the allogeneic splenocytes prior to irradiation largely eliminated their graft facilitating activity. Based upon the promising results of the pre-clinical murine studies, we initiated a phase I clinical trial of multiple infusions of irradiated allogeneic lymphocytes in patients who had relapsed after allogeneic BMT. Of 12 patients treated to date on this study, three have shown objective responses of their leukemia or lymphoma to multiple infusions of irradiated donor lymphocytes. We have initiated a new phase I clinical study to test the efficacy of multiple infusions of irradiated allogeneic cytotoxic T cells to facilitate engraftment in allogeneic transplantation. Successive cohorts of patients will be transplanted with allogeneic stem cells alone, or a combination of allogeneic stem cells and increasing numbers of irradiated allogeneic T cells. Irradiated allogeneic lymphocytes that retain short-term allo-specific cytotoxicity and lack the potential for clonal expansion in vivo can be considered as a novel form of immunotherapy with defined pharmacokinetics. Bone Marrow Transplantation (2000) 25, Suppl. 2, S20–S24.