Pando Alejandro, Reagan John L, Nevola Martha, Fast Loren D
Division of Hematology/Oncology, Rhode Island Hospital and the Warren Alpert School of Medicine at Brown University, One Hoppin Street, Coro West Suite 5.0.1, Providence, RI 02903 USA.
Exp Hematol Oncol. 2018 Oct 4;7:25. doi: 10.1186/s40164-018-0118-5. eCollection 2018.
Immunotherapeutic protocols have focused on identification of stimuli that induce effective anti-leukemic immune responses. One potent immune stimulus is the encounter with allogeneic cells. Our group previously showed that the infusion of haploidentical donor white blood cells (1-2 × 10 CD3+ cells/kg) into patients with refractory hematological malignancies induced responses of varying magnitude in over half of the patients. Because donor cells were eliminated within 2 weeks in these patients, it is presumed that the responses of recipient lymphocytes were critically important in achieving prolonged anti-leukemic responses.
The role of patient CD3+ cells in anti-leukemic responses was examined by isolating peripheral blood mononuclear cells from newly diagnosed leukemic patients. Immunophenotyping was performed on these peripheral blood mononuclear cells. CD3+ cells were isolated from the peripheral blood mononuclear cells and tested for their ability to proliferate and lyse autologous leukemic cells when stimulated with unrelated allogeneic cells.
Allostimulated CD3+ cells effectively generated cytolytic responses to autologous CD3-cells in 11/21 patients. Increased numbers of CD4+ cells expressing high levels of granzyme A, B and perforin and CD8+CD39+ cells were found in nonresponsive CD3+ cells.
These results indicate that CD3+ cells from leukemic patients are capable of generating anti-leukemic responses when stimulated with unrelated allogeneic cells. This model can be used to identify approaches using alloreactive responses by patient lymphocytes to enhance in vivo anti-leukemic responses.
免疫治疗方案一直专注于识别能诱导有效抗白血病免疫反应的刺激因素。一种强大的免疫刺激是与异基因细胞相遇。我们团队之前发现，向难治性血液系统恶性肿瘤患者输注单倍体相合供者白细胞（1 - 2×10个CD3⁺细胞/千克），超过半数患者出现了不同程度的反应。由于这些患者体内的供者细胞在2周内被清除，推测受者淋巴细胞的反应对于实现持久的抗白血病反应至关重要。
通过从新诊断的白血病患者中分离外周血单个核细胞，研究患者CD3⁺细胞在抗白血病反应中的作用。对这些外周血单个核细胞进行免疫表型分析。从外周血单个核细胞中分离出CD3⁺细胞，并检测其在用无关异基因细胞刺激时增殖和裂解自体白血病细胞的能力。
在21例患者中的11例中，异体刺激的CD3⁺细胞有效地对自体CD3⁻细胞产生了细胞溶解反应。在无反应的CD3⁺细胞中发现表达高水平颗粒酶A、B和穿孔素的CD4⁺细胞以及CD8⁺CD39⁺细胞数量增加。
这些结果表明，白血病患者的CD3⁺细胞在用无关异基因细胞刺激时能够产生抗白血病反应。该模型可用于确定利用患者淋巴细胞的同种异体反应来增强体内抗白血病反应的方法。
