Gause A, Yoshida N, Kappen C, Rajewsky K
Eur J Immunol. 1987 Jul;17(7):981-90. doi: 10.1002/eji.1830170714.
C57BL/6 mice were chronically treated with milligram doses of the noncytotoxic monoclonal anti-mu b antibody MB86 (IgG1, kappa) from birth or from fetal life. The spleens of the manipulated animals contained large numbers (25% as compared to control mice) of B lineage cells which expressed IgMb on the surface after overnight incubation in vitro. The spleens also contained B cells whose surface IgM was unreactive with antibody MB86. A few such cells were immortalized by cell fusion. They included cells secreting mu together with lambda 2 chains which apparently prevent recognition by antibody MB86, and a point mutant in the first constant domain of the mu chain, changing the b to the a allotype. Cells expressing MB86- surface IgM did not selectively expand under MB86 treatment over the first few months of life. Serum Ig levels in the manipulated mice were normal except for IgM which was undetectable in most instances. In some animals low levels of MB86- IgM molecules were produced. At 7 weeks of age, mice treated with MB86 from birth produced normal-size IgG anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) responses with the usual predominance of lambda 1 chain-bearing IgG1 antibodies. At the age of 5-6 months, and also in young mice treated with MB86 from fetal life, the responses were variable and presumably oligoclonal, with a tendency towards the production of antibodies with gamma 3 heavy and lambda 2 or lambda 3 light chains. We interpret these results to mean that B cells hit by antibody MB86 from the time of their generation become unresponsive to T cell-dependent stimulation, but are still able to expand. Occasionally, they escape functional suppression through class switching (to IgG3) upon mitogenic stimulation. At birth, C57BL/6 mice contain a mature B cell population which mediates normal immune responses under MB86 treatment and eventually dies out. Taken as a model of tolerance induction in B cells, the data provide evidence for "tolerant" cells and support the concept of an early phase of sensitivity to tolerance induction in B cell differentiation. The anti-NP response under MB86 treatment differed profoundly from control responses in idiotypic terms, but became normal as the animals recovered from suppression. This may reflect blockade by MB86 of idiotypic selection within the B cell population.
从出生或胎儿期开始，用毫克剂量的无细胞毒性单克隆抗μ b抗体MB86（IgG1，κ）对C57BL/6小鼠进行长期治疗。经处理的动物脾脏中含有大量（与对照小鼠相比为25%）B淋巴细胞系细胞，这些细胞在体外过夜培养后表面表达IgMb。脾脏中还含有表面IgM与抗体MB86无反应的B细胞。少数此类细胞通过细胞融合得以永生化。它们包括分泌μ链和λ 2链的细胞，这显然阻止了抗体MB86的识别，以及μ链第一个恒定结构域中的一个点突变体，将b同种异型转变为a同种异型。表达MB86 -表面IgM的细胞在生命的最初几个月中，在MB86处理下并未选择性扩增。除了在大多数情况下无法检测到的IgM外，经处理小鼠的血清Ig水平正常。在一些动物中产生了低水平的MB86 - IgM分子。在7周龄时，从出生就接受MB86治疗的小鼠产生了正常大小的IgG抗 -（4 - 羟基 - 3 - 硝基苯基）乙酰（NP）反应，通常以携带λ 1链的IgG1抗体为主。在5 - 6个月龄时，以及在从胎儿期就接受MB86治疗的幼鼠中，反应是可变的，推测为寡克隆性，倾向于产生具有γ 3重链和λ 2或λ 3轻链的抗体。我们将这些结果解释为，从产生时就受到抗体MB86作用的B细胞对T细胞依赖性刺激变得无反应，但仍能够扩增。偶尔，它们在有丝分裂刺激下通过类别转换（转换为IgG3）逃避功能抑制。出生时，C57BL/6小鼠含有一个成熟的B细胞群体，该群体在MB86处理下介导正常免疫反应，最终消失。作为B细胞耐受诱导的模型，这些数据为“耐受”细胞提供了证据，并支持了B细胞分化中对耐受诱导敏感性早期阶段的概念。在MB86处理下的抗NP反应在独特型方面与对照反应有很大不同，但随着动物从抑制中恢复而变得正常。这可能反映了MB86对B细胞群体内独特型选择的阻断。
