NEW STRATEGIES FOR USING ANTI-L3T4 TO STUDY MURINE LUPUS

NZB/NZW F1(B/W)小鼠的自身免疫性疾病可以被阻止 通过使用L3T4的单抗(Mab)持续治疗， 小鼠在人类体内的CD4同源物。在此基础上 ，我们将测试两个假设，这两个假设对于 对自身免疫发病机制的认识和对自身免疫的认识 单抗在人类体内的潜在用途。 假设1：抗L3T4单抗抑制小鼠狼疮 反映了对T细胞功能的抑制，不需要很深 L3T4+细胞耗竭。抗-HBs抑制自身免疫 L3T4可能是由于靶细胞耗尽或 对其功能的抑制。为了解决这个问题，我们将 确定抗L3T4的F(ab‘)2片段是否可以延缓 自身免疫，不会耗尽L3T4+细胞。我们还将 确定小剂量抗L3T4是否足以降低 但不能根除L3T4+细胞，可以延缓自身免疫 导致对正常免疫力的严重或持续的抑制。 以前研究这些方法的尝试是 对治疗的宿主免疫反应感到困惑。我们会 通过容忍只有一次兴奋的老鼠来绕过这个问题- L3T4单抗剂量。这些研究将为我们提供对 抗L3T4抗体抑制自身免疫的机制。他们 也将与人类使用抗CD4抗体的潜在用途有关， 通过测试两种快速可逆的治疗方法 将长期免疫抑制造成的风险降至最低，以及 通过展示主机问题的可能解决方案 对抗CD4单抗有免疫力。 假设2：早期B细胞成熟和晚期B细胞恶性 在B/W小鼠中是独立的T细胞帮助。几个B细胞 异常可能有助于B/W小鼠的自身免疫。 这些包括：自发的和有丝分裂原诱导的B细胞 多动症；(Ii)年龄相关的从免疫球蛋白M转换为免疫球蛋白 产量：(3)Ly-1+B细胞增加；(4)B细胞 恶性肿瘤。我们将确定这些B细胞 像自身免疫性疾病一样，异常依赖于L3T4+ T细胞或它们是否独立发生。这将是 用单抗去除B/W小鼠L3T4+细胞 在生命的早期就开始(如果需要的话，在子宫里)。这些研究将 通过帮助了解小鼠狼疮的发病机制 确定L3T4+T细胞在发病的哪个阶段发挥其功能 影响力。他们还将阐明特定B细胞的作用 自身免疫性疾病的表达缺陷，他们将 识别潜在的病理性B细胞异常 受到T细胞调节改变的影响，但更需要 另类疗法。

Autoimmune disease in NZB/NZW F1 (B/W) mice can be arrested by sustained treatment with monoclonal antibodies (Mab) to L3T4, the mouse homologue for CD4 in humans. Based on this observation, we will test two hypotheses that are important to an understanding of the pathogenesis of autoimmunity and to the potential use of MAb to CD4 in humans. Hypothesis 1: Suppression of murine lupus with MAb to L3T4 reflects inhibition of T cell function and does not require profound depletion of L3T4+ cells. Suppression of autoimmunity by anti- L3T4 could be due either to depletion of target cells or to inhibition of their function. To resolve this issue, we will determine whether F(ab')2 fragments of anti-L3T4 can retard autoimmunity without depleting L3T4+ cells. We will also determine whether low doses of anti-L3T4, sufficient to reduce but not eradicate L3T4+ cells, can retard autoimmunity without causing severe or sustained suppression of normal immunity. Previous attempts to examine these approaches have been confounded by a host immune response to therapy. We will circumvent this problem by tolerizing mice with a single high- dose of MAb to L3T4. These studies will provide insight into the mechanism by which anti-L3T4 suppresses autoimmunity. They will also be relevant to the potential use of anti-CD4 in humans, by testing two rapidly reversible approaches to therapy that will minimize the risks caused by prolonged immune suppression, and by demonstrating a possible solution to the problem of host immunity to anti-CD4 MAb. Hypothesis 2: Early B cell maturation and late B cell malignancy in B/W mice is independent of T cell help. Several B cell abnormalities could contribute to autoimmunity in B/W mice. These include: spontaneous and mitogen-induced B cell hyperactivity; (ii) age-dependent switch from IgM to IgG production: (iii) increased Ly-1+B cells; and (iv) B cell malignancies. We will determine whether these B cell abnormalities are, like autoimmune disease, dependent on L3T4+ T cells or whether they occur independently. This will be accomplished by using MAb to deplete L3T4+ cells from B/W mice beginning early in life (in utero, if necessary). These studies will provide insight into the pathogenesis of murine lupus by helping to determine at what stage in pathogenesis L3T4+ T cells exert their influence. They will also clarify the role of specific B cell defects in the expression of autoimmune disease, and they will identify potentially pathologic B cell abnormalities that would not be affected by altering T cell regulation but rather would require alternative therapies.