Kuzmin A I, Galenko O, Eisensmith R C
Institute for Gene Therapy and Molecular Medicine, Mt. Sinai School of Medicine, New York, New York 10029, USA.
Mol Ther. 2001 Mar;3(3):293-301. doi: 10.1006/mthe.2000.0258.
Immune responses against E1-deleted adenovirus vectors and/or their transgene products result in the rapid elimination of vector-transduced cells and the generation of neutralizing antibodies. Different strategies of immunomodulation to stabilize transgene expression at therapeutic levels and to permit productive vector readministration have been examined. Our previous studies have shown that depletion of macrophages from spleen and liver decreases hepatic inflammation, significantly prolongs transgene expression, and delays the onset of humoral immune responses after systemic administration of an E1-deleted adenovirus vector. In the present study, we have examined the effects of macrophage depletion in combination with temporary blockade of CD40 ligation on E1-deleted adenovirus vector-mediated gene transfer. Alone, each of these treatments significantly inhibited the humoral immune response against the transgene product and prolonged its expression. Together, these treatments completely stabilized transgene expression and inhibited the production of neutralizing anti-adenovirus antibodies, permitting successful vector readministration. Animals rendered immunologically unresponsive to vector and transgene antigens regained their ability to mount productive immune responses against the vector after recovery of immune function, but remained unresponsive to the transgene product. These experiments demonstrate that this treatment is transient and antigen-specific.
针对E1缺失腺病毒载体和/或其转基因产物的免疫反应会导致载体转导细胞迅速被清除，并产生中和抗体。人们已经研究了不同的免疫调节策略，以将转基因表达稳定在治疗水平，并允许进行有效的载体再次给药。我们之前的研究表明，从脾脏和肝脏中清除巨噬细胞可减轻肝脏炎症，显著延长转基因表达，并延迟全身给予E1缺失腺病毒载体后体液免疫反应的发生。在本研究中，我们研究了巨噬细胞清除与临时阻断CD40连接相结合对E1缺失腺病毒载体介导的基因转移的影响。单独使用时，每种治疗方法均显著抑制了针对转基因产物的体液免疫反应，并延长了其表达。这些治疗方法共同作用，完全稳定了转基因表达，并抑制了中和抗腺病毒抗体的产生，从而允许成功进行载体再次给药。对载体和转基因抗原产生免疫无反应的动物在免疫功能恢复后重新获得了对载体产生有效免疫反应的能力，但对转基因产物仍无反应。这些实验表明，这种治疗是短暂的且具有抗原特异性。
