NEW STRATEGIES FOR USING ANTI-L3T4 TO STUDY MURINE LUPUS

NZ B/NZW F1（B/W）小鼠的自身免疫性疾病可被阻止 通过用抗L3 T4的单克隆抗体（Mab）持续治疗， 人类CD 4的小鼠同源物。 基于此 观察，我们将测试两个假设是重要的， 了解自身免疫的发病机制， 在人类中抗CD 4单克隆抗体的潜在用途。 假设1：抗L3 T4单克隆抗体对鼠狼疮的抑制 反映了T细胞功能的抑制，并且不需要深刻的 L3 T4+细胞的耗竭。 通过抗- L3 T4可能是由于靶细胞耗竭或 抑制其功能。 为了解决这个问题，我们将 确定抗L3 T4的F（ab '）2片段是否可以阻滞 自身免疫而不消耗L3 T4+细胞。 我们还将 确定是否低剂量的抗L3 T4，足以减少 但不能根除L3 T4+细胞，可以延缓自身免疫， 导致严重或持续的正常免疫抑制。 以前尝试检查这些方法， 被宿主对治疗的免疫反应所混淆。 我们将 通过让小鼠耐受一种高浓度的 MAb剂量至L3 T4。 这些研究将提供深入了解 抗L3 T4抗体抑制自身免疫的机制。 他们 也将与抗CD 4在人类中的潜在用途相关， 通过测试两种快速可逆的治疗方法， 最大限度地减少长期免疫抑制引起的风险， 通过展示一种可能的解决方案， 抗CD 4单克隆抗体免疫。 假设2：早期B细胞成熟和晚期B细胞恶性 在B/W小鼠中不依赖于T细胞的帮助。 几个B细胞 异常可能导致B/W小鼠的自身免疫。 这些包括：自发和丝裂原诱导的B细胞 多动;（ii）年龄依赖性从IgM转换为IgG 产生：（iii）增加的Ly-1+B细胞;和（iv）B细胞 恶性肿瘤。 我们将确定这些B细胞 异常，像自身免疫性疾病，依赖于L3 T4 + T细胞或它们是否独立发生。 这将是 通过使用MA B耗竭B/W小鼠的L3 T4+细胞完成 开始于生命早期（如有必要，在子宫内）。 这些研究将 通过帮助了解小鼠狼疮的发病机制， 确定L3 T4 + T细胞在发病机制的哪个阶段发挥其 影响力的社会 他们还将阐明特定的B细胞的作用 自身免疫性疾病的表达缺陷， 识别潜在的病理性B细胞异常， 受T细胞调节改变的影响，而是需要 替代疗法

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.