Milich D R, Jones J E, Hughes J L, Maruyama T, Price J, Melhado I, Jirik F
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037.
J Immunol. 1994 Jan 15;152(2):455-66.
We previously developed a transgenic (Tg) murine lineage (B10.S-Tg31e), which secretes the hepatitis B e Ag (HBeAg) into the serum at a concentration of 10 ng/ml. This serum concentration was sufficient to render B10.S-Tg31e mice functionally tolerant at the T cell but not B cell level. To determine the tolerogenic potential of an intracellular form of this Ag, namely the hepatitis B core Ag (HBcAg), expressed outside the thymus, the B10.S-Tg10c lineage was developed. In B10.S-Tg10c mice the HBcAg is expressed as an intracellular "self"-Ag predominantly in the liver, and cannot be detected in the serum, the thymus or in nonthymic lymphoid tissue. Despite the liver-specific and intracellular location of this transgenic self-protein, B10-STg10c mice demonstrate a significant degree of HBcAg-specific T cell tolerance at the level of T cell proliferation. Similarly, in vivo anti-HBc antibody production after HBcAg immunization is significantly reduced as compared with non-Tg littermate controls. No spontaneous anti-HBc antibody is produced in B10.S-Tg10c mice, however, adoptive transfer of HBcAg-specific T cells from non-Tg B10.S mice elicits anti-HBc specific "autoantibody" production. Interestingly, antibodies with specificity for the HBeAg as well as the HBcAg are produced. Antibody production in B10.S-Tg10c mice adoptively transferred with T cells indicates that sufficient native HBcAg can gain access to the extracellular compartment to engage HBcAg-specific B cells that are clearly not tolerant in this model. No liver injury was observed as a consequence of HBcAg expression, even in B10.S-Tg10c mice adoptively transferred with HBcAg-specific T cells. Unless HBcAg is unique in this regard, these results suggest that organ-specific, intracellular self-Ag may be released during normal cell turnover in sufficient concentrations to elicit systemic T cell tolerance. B10.S-Tg10c mice also serve as an immunologic model system for chronic infection with the HBeAg-negative mutant of the hepatitis B virus.
我们之前培育出一种转基因（Tg）小鼠品系（B10.S-Tg31e），其能以10 ng/ml的浓度将乙肝e抗原（HBeAg）分泌到血清中。这种血清浓度足以使B10.S-Tg31e小鼠在T细胞水平而非B细胞水平产生功能性耐受。为了确定这种抗原的细胞内形式，即乙肝核心抗原（HBcAg）在胸腺外表达时的致耐受性潜力，我们培育了B10.S-Tg10c品系。在B10.S-Tg10c小鼠中，HBcAg主要在肝脏中作为细胞内“自身”抗原表达，在血清、胸腺或非胸腺淋巴组织中无法检测到。尽管这种转基因自身蛋白具有肝脏特异性且位于细胞内，但B10-STg10c小鼠在T细胞增殖水平上表现出显著程度的HBcAg特异性T细胞耐受。同样，与非转基因同窝对照相比，HBcAg免疫后体内抗HBc抗体的产生显著减少。B10.S-Tg10c小鼠不产生自发的抗HBc抗体，然而，从非转基因B10.S小鼠过继转移HBcAg特异性T细胞会引发抗HBc特异性“自身抗体”的产生。有趣的是，产生了对HBeAg以及HBcAg具有特异性的抗体。用T细胞过继转移的B10.S-Tg10c小鼠中的抗体产生表明，足够的天然HBcAg能够进入细胞外区室，以激活在此模型中显然不耐受的HBcAg特异性B细胞。即使在过继转移了HBcAg特异性T细胞的B10.S-Tg10c小鼠中，也未观察到因HBcAg表达而导致的肝损伤。除非HBcAg在这方面具有独特性，这些结果表明，器官特异性的细胞内自身抗原可能在正常细胞更新过程中以足够的浓度释放，从而引发全身性T细胞耐受。B10.S-Tg10c小鼠还可作为乙肝病毒HBeAg阴性突变体慢性感染的免疫模型系统。
