Leitner Wolfgang W, Hwang Leroy N, Bergmann-Leitner Elke S, Finkelstein Steven E, Frank Stephan, Restifo Nicholas P
Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 2B42 Bethesda, MD 20892-1502, USA.
Vaccine. 2004 Mar 29;22(11-12):1537-44. doi: 10.1016/j.vaccine.2003.10.013.
Alphaviral replicons can increase the efficacy and immunogenicity of naked nucleic acid vaccines. To study the impact of apoptosis on this increased effectiveness, we co-delivered an anti-apoptotic gene (Bcl-X(L)) with the melanocyte/melanoma differentiation antigen TRP-1. Although cells co-transfected with Bcl-X(L) lived longer, produced more antigen and elicited increased antibody production in vivo, co-delivery of pro-survival Bcl-X(L) with antigen significantly reduced the ability of the replicase-based vaccine to protect against an aggressive tumor challenge. These data show for the first time that the induction of apoptotic cell death of transfected cells in vivo is required for the increased effectiveness of replicase-based vaccines. Our findings also provide an explanation for the paradoxical observation that replicase-based DNA vaccines are much more immunogenic than conventional constructs despite reduced antigen production.
甲病毒复制子可提高裸核酸疫苗的效力和免疫原性。为研究细胞凋亡对这种效力增强的影响，我们将抗凋亡基因（Bcl-X(L)）与黑素细胞/黑色素瘤分化抗原TRP-1共同递送。虽然与Bcl-X(L)共转染的细胞存活时间更长，产生了更多抗原并在体内引发了抗体产生增加，但将促存活的Bcl-X(L)与抗原共同递送显著降低了基于复制酶的疫苗抵御侵袭性肿瘤攻击的能力。这些数据首次表明，体内转染细胞的凋亡性细胞死亡诱导对于基于复制酶的疫苗效力增强是必需的。我们的研究结果还为一个矛盾的观察结果提供了解释，即尽管抗原产生减少，但基于复制酶的DNA疫苗比传统构建体具有更强的免疫原性。
