Vemuru R P, Davidson A, Aragona E, Chowdhury J R, Burk R D, Gupta S
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461.
FASEB J. 1992 Jul;6(10):2836-42. doi: 10.1096/fasebj.6.10.1634046.
Development of a host immune response against gene products expressed by genetically modified cells could be a serious limitation for gene therapy. During examination of whether site-specific differences in antigen presentation could regulate the host immune response, we observed an absence of antibodies against hepatitis B virus surface antigen (HBsAg) when HBsAg producing transgenic hepatocytes were transplanted into the spleen. Intrasplenic transplantation resulted in translocation of a large number of cells into the portal vascular bed and liver sinusoids. In these recipients, HBsAg secreted by the transplanted hepatocytes circulated indefinitely in the blood. In contrast, subcutaneous or intraperitoneal transplantation of the transgenic hepatocytes induced an anti-HBs response, followed by clearance of serum HBsAg. Rechallenge with HBsAg in a highly immunogenic form failed to break the tolerance in intrasplenic hepatocyte recipients even though these animals responded to another antigen (keyhole limpet hemocyanin). Immunization with HBsAg in intraperitoneal recipients of HBsAg producing hepatocytes further elevated anti-HBs titers. Our results indicate that hepatocyte transplantation into the portal vascular bed via injection into the spleen can confer immune tolerance to secreted heterologous antigens. This finding should have important implications for human gene therapy as well as for analyzing the mechanisms of immune tolerance.
针对基因改造细胞所表达基因产物产生宿主免疫反应，可能会成为基因治疗的一个严重限制因素。在研究抗原呈递的位点特异性差异是否能够调节宿主免疫反应的过程中，我们观察到，当将产生乙型肝炎病毒表面抗原（HBsAg）的转基因肝细胞移植到脾脏时，未出现针对HBsAg的抗体。脾内移植导致大量细胞转移至门静脉血管床和肝血窦。在这些受体中，移植的肝细胞分泌的HBsAg在血液中无限期循环。相比之下，转基因肝细胞的皮下或腹腔内移植则诱导了抗-HBs反应，随后血清HBsAg被清除。即使这些动物对另一种抗原（钥孔戚血蓝蛋白）有反应，但以高免疫原性形式再次给予HBsAg并不能打破脾内肝细胞受体的耐受性。在产生HBsAg的肝细胞的腹腔内受体中用HBsAg进行免疫接种可进一步提高抗-HBs滴度。我们的结果表明，通过注射到脾脏将肝细胞移植到门静脉血管床可赋予对分泌的异源抗原的免疫耐受性。这一发现对于人类基因治疗以及分析免疫耐受机制均应具有重要意义。
