Chimeric cytotoxin IL2-PE40 delays and mitigates adjuvant-induced arthritis in rats.
Chimeric cytotoxin IL2-PE40 delays and mitigates adjuvant-induced arthritis in rats.
复制标题
嵌合细胞毒素 IL2-PE40 可延迟并减轻佐剂诱导的大鼠关节炎。
DOI：
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发表时间：
1989
影响因子：
11.1
通讯作者：
I. Pastan
中科院分区：
文献类型：
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作者：
J. Case;H. Lorberboum;R. Lafyatis;D. Fitzgerald;R. Wilder;I. Pastan
大鼠的佐剂性关节炎是一种依赖t细胞的“自身免疫性”疾病，与几种形式的人类关节炎非常相似。注射分枝杆菌佐剂导致t细胞活化和增殖，在这一过程中，白细胞介素2 （IL-2）受体的重新表达起着关键作用。随后大量单核细胞浸润关节，最终导致关节完全破坏。由于T淋巴细胞辅助/诱导剂亚群的激活对疾病的建立至关重要，我们推断IL2-PE40是一种细胞毒性IL-2假单胞菌外毒素融合蛋白，其靶向毒素的膜穿透和adp -核糖化结构域，以携带IL-2受体的细胞为靶点，将是一种有效的特异性治疗方法。注射佐剂的大鼠随机接受il - 2- pe40、磷酸盐缓冲盐水或两种与il - 2- pe40相关的对照蛋白中的任何一种治疗，但缺乏受体结合部分或酶活性毒素结构域，并且先前在体外证明缺乏细胞毒性。根据临床、组织学和放射学标准，在明确的临床疾病建立之前给予腹腔注射il - 2- pe40证明是佐剂性关节炎的有效和特异性调节剂。我们的数据表明，IL2-PE40可能对那些活化t细胞起重要作用的疾病有效。
Adjuvant arthritis in rats is a T-cell dependent "autoimmune" disease with close similarities to several forms of human arthritis. Injection of mycobacterial adjuvant leads to T-cell activation and proliferation, processes in which the de novo expression of the interleukin 2 (IL-2) receptor plays a pivotal role. The subsequent massive mononuclear cell infiltration of the joints ultimately results in complete joint destruction. Because activation of the helper/inducer subset of T lymphocytes is critical to the establishment of disease, we reasoned that IL2-PE40, a cytotoxic IL-2-Pseudomonas exotoxin fusion protein that targets the membrane-penetration and ADP-ribosylation domains of the toxin to cells bearing the IL-2 receptor, would be an effective and specific therapy. Adjuvant-injected rats were randomized to treatment with IL2-PE40, phosphate-buffered saline, or either of two control proteins related to IL2-PE40 but lacking either the receptor-binding moiety or an enzymatically active toxin domain and previously demonstrated to lack cytotoxicity in vitro. Intraperitoneal IL2-PE40 given before the establishment of overt clinical disease proved an effective and specific modifier of adjuvant arthritis by clinical, histological, and radiographic criteria. Our data suggest that IL2-PE40 may be effective in those diseases in which activated T-cells play an important role.