Kobayashi Masayuki, Takaori-Kondo Akifumi, Fukunaga Keiko, Miyoshi Hiroyuki, Uchiyama Takashi
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Int J Hematol. 2004 May;79(4):377-83. doi: 10.1532/ijh97.03120.
Gene-modified dendritic cells (DCs) are promising targets for cancer immunotherapy. In this study, we demonstrated that lentiviral transduction of DCs with the gp34/OX40L gene, one of the costimulatory molecules, facilitates alloreactive CD4+ T-cell response in vitro. We achieved a 20% to 40% efficiency of gp34/OX40L gene transfer into DCs by the lentiviral vector, and lentiviral gp34/OX40L gene transfer did not alter the surface phenotype of either immature or mature DCs, suggesting that expression of gp34/OX40L did not induce the maturation of immature DCs and that gp34/OX40L-transduced DCs could fully differentiate into mature DCs. gp34/OX40L gene transfer facilitated an allogeneic CD4+ T-cell response in vitro by mature DCs but not by immature DCs. Dose escalation of the transgene induced an increasing amount of gp34/OX40L expression, leading to an increasing level of up-regulation of the allogeneic CD4+ T-cell response. The addition of anti-gp34 monoclonal antibody totally abrogated this up-regulation. These results suggest that this facilitation of allogeneic CD4+ T-cell response is specifically dependent on gp34/OX40L expressed on transduced DCs. Taken together, our findings show that gp34/ OX40L plays an important role in allogeneic CD4+ T-cell activation by DCs and that lentiviral gp34/OX40L gene transfer into DCs may be a useful strategy for cancer immunotherapy.
基因修饰的树突状细胞（DCs）是癌症免疫治疗的有前景的靶点。在本研究中，我们证明用共刺激分子之一的gp34/OX40L基因对DCs进行慢病毒转导，可在体外促进同种异体反应性CD4⁺ T细胞应答。通过慢病毒载体，我们实现了gp34/OX40L基因向DCs的20%至40%的转导效率，并且慢病毒gp34/OX40L基因转导未改变未成熟或成熟DCs的表面表型，这表明gp34/OX40L的表达未诱导未成熟DCs的成熟，且gp34/OX40L转导的DCs可完全分化为成熟DCs。gp34/OX40L基因转导在体外促进了成熟DCs而非未成熟DCs的同种异体CD4⁺ T细胞应答。转基因的剂量递增诱导了gp34/OX40L表达量增加，导致同种异体CD4⁺ T细胞应答上调水平增加。添加抗gp34单克隆抗体完全消除了这种上调。这些结果表明，这种对同种异体CD4⁺ T细胞应答的促进作用特别依赖于转导DCs上表达的gp34/OX40L。综上所述，我们的研究结果表明gp34/OX40L在DCs介导的同种异体CD4⁺ T细胞活化中起重要作用，并且将慢病毒gp34/OX40L基因转导至DCs可能是一种有用的癌症免疫治疗策略。
