Boyer M W, Vallera D A, Taylor P A, Gray G S, Katsanis E, Gorden K, Orchard P J, Blazar B R
Department of Pediatrics, University of Minnesota Hospital and Clinic, Minneapolis, USA.
Blood. 1997 May 1;89(9):3477-85.
Relapse is more frequent after autologous than allogeneic bone marrow transplantation (BMT), due in part to lack of T-lymphocyte mediated allogeneic graft-versus-leukemia (GVL) effects. Infusions of leukemia-reactive T cells to patients after autologous BMT may be a means for providing a GVL effect. Costimulation of T cells by binding of the CD28 receptor on T cells with B7-counter receptors on antigen presenting cells amplifies antigen-specific T-cell responses. To enhance generation of leukemia reactive cytotoxic T lymphocytes (CTL), the murine B7-1- and B7-2-costimulatory molecule cDNAs were introduced into the MHC class I+, class II-, murine meyloid leukemia cell line C1498. B7-1 expression greatly enhanced the ability of the leukemia cells to generate and expand leukemia reactive CTL in vitro. A highly cytolytic and C1498 specific CD8+ CTL line was generated by B7-1 costimulation. This CTL line proliferated autonomously and produced interleukin-2 when provided B7-1 or B7-2 costimulation by C1498 leukemia cells. To test the in vivo antileukemia properties of this CTL line, irradiated syngeneic BMT recipients were given graded doses of leukemia cells on day 0, followed by CTL infusions beginning on day 1 post-BMT. Recipients of 10(7) CTL had a 3 log reduction in leukemia burden such that 100% of mice were protected from a supralethal leukemic cell dose. Sustained immune responses were detectable up to 3 months postinfusion of the CTL line. B7-1 or B7-2 costimulation in vivo did not augment antileukemia effects of infused CTL post BMT. These results suggest that B7 costimulation of leukemia reactive CTL may be important for their ex vivo generation and expansion for use in human adoptive immunotherapy of leukemia.
自体骨髓移植（BMT）后复发比异基因骨髓移植更频繁，部分原因是缺乏T淋巴细胞介导的异基因移植物抗白血病（GVL）效应。自体BMT后给患者输注白血病反应性T细胞可能是提供GVL效应的一种方法。T细胞上的CD28受体与抗原呈递细胞上的B7配体受体结合对T细胞的共刺激可增强抗原特异性T细胞反应。为了增强白血病反应性细胞毒性T淋巴细胞（CTL）的产生，将小鼠B7-1和B7-2共刺激分子cDNA导入MHC I类阳性、II类阴性的小鼠髓样白血病细胞系C1498。B7-1的表达极大地增强了白血病细胞在体外产生和扩增白血病反应性CTL的能力。通过B7-1共刺激产生了一种高度细胞溶解且具有C1498特异性的CD8+CTL系。当C1498白血病细胞提供B7-1或B7-2共刺激时，该CTL系可自主增殖并产生白细胞介素-2。为了测试该CTL系的体内抗白血病特性，在第0天给经照射的同基因BMT受体给予分级剂量的白血病细胞，然后在BMT后第1天开始输注CTL。接受10⁷个CTL的受体白血病负荷降低了3个对数，使得100%的小鼠免受超致死剂量白血病细胞的侵害。在输注CTL系后长达3个月可检测到持续的免疫反应。体内B7-1或B7-2共刺激并未增强BMT后输注CTL的抗白血病作用。这些结果表明，B7对白血病反应性CTL的共刺激对于其在体外的产生和扩增可能很重要，可用于人类白血病的过继免疫治疗。
