von Borstel R C, Diner U E, Waters C A, Diener E
Cell Immunol. 1983 Oct 15;81(2):229-42. doi: 10.1016/0008-8749(83)90231-9.
Hapten-specific B-cell tolerance may be induced by nonimmunogenic hapten derivatives of carboxylmethylcellulose or methylcellulose (MC) in adult, neonatal, or irradiated fetal liver reconstituted mice. Such tolerance was shown to occur independent of T cells, and a receptor blockade has been ruled out as a causative mechanism. Oxidation and subsequent reduction of the vicinal hydroxyl groups of both carriers significantly reduces their tolerogenic potential in adult mice, yet their hapten derivatives remain nonimmunogenic. Such chemical modification of the carrier does not affect the molecular weight and not only does not reduce the binding avidity but increases it for either free antibody- or antigen-binding cells. We have examined the ability of the immature immune system to functionally discriminate between the nominal and the chemically modified hapten conjugate. Like adult mice, the immunologically immature animals were invariably capable of distinguishing between the tolerogenic and the nontolerogenic carrier. Mice treated during ontogenic development with 2,4-dinitrophenyl (DNP)-MC were found to be hapten specifically tolerant when challenged at 4 weeks of age with the TI-2 antigen DNP-Ficoll (F) but not when challenged with the polyclonal activator lipopolysaccharide (LPS) or the TI-1 antigen DNP-Brucella. Moreover, neonatal mice treated for 8 weeks with 2,4,6-trinitrophenyl-ovalbumin (TNP-OVA) were hapten specifically tolerant when challenged with TNP-OVA or the TI-1 antigen TNP-LPS but responded to a challenge with the TI-2 antigen TNP-F. These data suggest that B-cell tolerance in adult as well as in immunologically immature mice is not only carrier dependent but, in addition, that the carrier selects the B subpopulation to be rendered unresponsive. The most popular version of the clonal abortion hypothesis puts no constraints upon the nature of the antigen as long as the B cell is ontogenically "predisposed" toward being rendered unresponsive upon contact with a ligand of sufficiently high binding avidity. Our data are at variance with this prediction.
在成年、新生或经辐照后用胎肝重建的小鼠中，羧甲基纤维素或甲基纤维素（MC）的非免疫原性半抗原衍生物可诱导半抗原特异性B细胞耐受。已证明这种耐受的发生不依赖于T细胞，并且已排除受体阻断作为致病机制。两种载体的邻位羟基氧化并随后还原会显著降低它们在成年小鼠中的致耐受潜力，但其半抗原衍生物仍无免疫原性。载体的这种化学修饰不影响分子量，不仅不会降低结合亲和力，反而会增加对游离抗体或抗原结合细胞的结合亲和力。我们研究了未成熟免疫系统在功能上区分名义上的和化学修饰的半抗原偶联物的能力。与成年小鼠一样，免疫未成熟的动物始终能够区分致耐受和非致耐受的载体。发现在个体发育过程中用2,4-二硝基苯基（DNP）-MC处理的小鼠，在4周龄时用TI-2抗原DNP-菲可（F）攻击时具有半抗原特异性耐受，但用多克隆激活剂脂多糖（LPS）或TI-1抗原DNP-布鲁氏菌攻击时则不然。此外，用2,4,6-三硝基苯基-卵清蛋白（TNP-OVA）处理8周的新生小鼠，在用TNP-OVA或TI-1抗原TNP-LPS攻击时具有半抗原特异性耐受，但对TI-2抗原TNP-F的攻击有反应。这些数据表明，成年小鼠以及免疫未成熟小鼠中的B细胞耐受不仅依赖于载体，而且载体还选择使其无反应的B亚群。克隆流产假说最流行的版本对抗原的性质没有限制，只要B细胞在个体发育上“倾向于”在接触具有足够高结合亲和力的配体时变得无反应。我们的数据与这一预测不一致。
