Rabinovitch A, Suarez W L, Qin H Y, Power R F, Badger A M
Department of Medicine, University of Alberta, Edmonton, Canada.
J Autoimmun. 1993 Feb;6(1):39-49. doi: 10.1006/jaut.1993.1004.
Immunomodulatory azaspirane compounds have immunosuppressive activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental autoimmune encephalomyelitis. The mechanism of action of azaspiranes appears to be the induction of antigen non-specific (natural) suppressor cell activity. In this study, we tested the azaspirane, SK&F 106610 in an animal model of autoimmune (type 1) diabetes, the BB rat. Oral administration of SK&F 106610 (15 mg/kg/day) to diabetes-prone BB rats, from age 30 days, significantly decreased diabetes incidence at 100 days from 80% (24 of 30 control rats) to 32% (10 of 31 drug-treated rats, P < 0.001). Protection from diabetes by SK&F 106610 was accompanied by decreased lymphocytic infiltration of the pancreatic islets (insulitis). No changes occurred in splenic T cell, B cell or macrophage subsets, or in proliferative responses to the mitogens lipopolysaccharide and concanavalin A (Con-A). Cell mixing experiments in vitro, however, revealed increased antigen non-specific suppressor activity (suppression of splenic lymphoproliferative response to Con-A) in spleens of SK&F 106610-treated rats. The suppressor cell activity was enriched in a low density fraction of splenic cells relatively depleted of T cells, B cells, macrophages and natural killer cells. These results indicate that the azaspirane compound, SK&F 106610 can prevent insulitis and autoimmune diabetes in BB rats and that these actions may be related to the activation of non-specific (natural) suppressor cells.
免疫调节氮杂环丙烷化合物在自身免疫性疾病的动物模型中具有免疫抑制活性，如佐剂诱导的关节炎和实验性自身免疫性脑脊髓炎。氮杂环丙烷的作用机制似乎是诱导抗原非特异性（天然）抑制细胞活性。在本研究中，我们在自身免疫性（1型）糖尿病动物模型BB大鼠中测试了氮杂环丙烷SK&F 106610。从30日龄开始，对易患糖尿病的BB大鼠口服SK&F 106610（15毫克/千克/天），100天时糖尿病发病率从80%（30只对照大鼠中的24只）显著降低至32%（31只药物治疗大鼠中的10只，P<0.001）。SK&F 106610对糖尿病的保护作用伴随着胰岛淋巴细胞浸润（胰岛炎）的减少。脾脏T细胞、B细胞或巨噬细胞亚群，以及对有丝分裂原脂多糖和伴刀豆球蛋白A（Con-A）的增殖反应均未发生变化。然而，体外细胞混合实验显示，SK&F 106610处理的大鼠脾脏中抗原非特异性抑制活性增加（抑制脾脏淋巴细胞对Con-A的增殖反应）。抑制细胞活性在脾脏细胞的低密度部分富集，该部分相对缺乏T细胞、B细胞、巨噬细胞和自然杀伤细胞。这些结果表明，氮杂环丙烷化合物SK&F 106610可以预防BB大鼠的胰岛炎和自身免疫性糖尿病，并且这些作用可能与非特异性（天然）抑制细胞的激活有关。
