Kennedy M K, Dal Canto M C, Trotter J L, Miller S D
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611.
J Immunol. 1988 Nov 1;141(9):2986-93.
These studies were designed to examine immunologic means of regulating the clinical course of murine chronic-relapsing experimental allergic encephalomyelitis (R-EAE). We asked whether induction of specific immune tolerance to the major CNS myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP), could inhibit the development of R-EAE. Neuroantigen-specific tolerance was induced in SJL/J mice in a dose-dependent manner by the i.v. injection of mouse spinal cord homogenate-coupled syngeneic splenocytes (MSCH-SP) on day -7 relative to immunization on days 0 and +7. Sham-tolerized controls developed significant MBP- and PLP-specific DTH responses before the onset of clinical R-EAE. In contrast, MSCH-SP tolerized mice exhibited a dramatically reduced incidence of clinical and histologic signs of disease which correlated with the failure to develop MBP- and PLP-specific DTH responses. In 10 separate experiments, 118/149 (79%) of control mice, but only 22/137 (16%) of tolerized mice developed clinical R-EAE. Tolerance took time to develop and lasted at least 4 wk as mice injected with Ag-coupled splenocytes on day -1 relative to immunization remained susceptible to R-EAE, whereas mice injected on days -7, -14, or -28 were resistant. Tolerance induction required neuroantigens as injection of splenocytes coupled with a syngeneic mouse kidney homogenate failed to significantly alter the incidence of R-EAE or the development of neuroantigen-specific DTH responses. Thus, induction of R-EAE can be specifically and significantly regulated after the i.v. injection of splenocytes coupled with a crude, heterogeneous mixture of neuroantigens (i.e. MSCH).
这些研究旨在探讨调节小鼠慢性复发性实验性变应性脑脊髓炎（R-EAE）临床病程的免疫方法。我们研究了对主要中枢神经系统髓鞘蛋白，即髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP）诱导特异性免疫耐受是否能抑制R-EAE的发展。在相对于第0天和第+7天免疫的第-7天，通过静脉注射小鼠脊髓匀浆偶联的同基因脾细胞（MSCH-SP），以剂量依赖的方式在SJL/J小鼠中诱导神经抗原特异性耐受。在临床R-EAE发作前，假耐受对照组出现了显著的MBP和PLP特异性迟发型超敏反应（DTH）。相比之下，MSCH-SP耐受小鼠的临床和组织学疾病体征发生率显著降低，这与未能产生MBP和PLP特异性DTH反应相关。在10项独立实验中，149只对照小鼠中有118只（79%）发生了临床R-EAE，但耐受小鼠中只有22只（137只中的16%）发病。耐受的形成需要时间，且至少持续4周，因为相对于免疫而言在第-1天注射抗原偶联脾细胞的小鼠对R-EAE仍易感，而在第-7天、-14天或-28天注射的小鼠则具有抗性。耐受诱导需要神经抗原，因为注射与同基因小鼠肾匀浆偶联的脾细胞未能显著改变R-EAE的发生率或神经抗原特异性DTH反应的发展。因此，静脉注射与神经抗原的粗制、异质混合物（即MSCH）偶联的脾细胞后，R-EAE的诱导可得到特异性和显著的调节。
