Khoury S J, Hancock W W, Weiner H L
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
J Exp Med. 1992 Nov 1;176(5):1355-64. doi: 10.1084/jem.176.5.1355.
Experimental autoimmune encephalomyelitis (EAE) in the Lewis rat is a self-limited inflammatory process localized to the central nervous system that is induced by the injection of myelin basic protein (MBP) in adjuvant. Oral administration of MBP suppresses EAE, and this suppression is mediated by CD8+ T cells that adoptively transfer protection and suppress both in vitro and in vivo by the release of transforming growth factor (TGF) beta after antigen-specific triggering. Furthermore, oral tolerance to MBP is enhanced by the concomitant oral administration of lipopolysaccharide (LPS). The present study was undertaken to determine whether the disease course in EAE and its suppression by oral tolerization to MBP is associated with distinct patterns of cytokine expression in the target organ. Detailed immunohistology of the brain was performed at the peak of clinical disease (day 14 after immunization) and after recovery (day 18) in control (ovalbumin [OVA]-fed), MBP-fed, and MBP plus LPS-fed animals. Brains from OVA-fed animals at the peak of disease showed perivascular infiltration with activated mononuclear cells which secreted the inflammatory cytokines interleukins (IL) 1, 2, 6, 8, TNF-alpha, and interferon gamma. The inhibitory cytokines TGF-beta and IL-4, and prostaglandin E2 (PGE2) were absent. In MBP orally tolerized animals there was a marked reduction of the perivascular infiltrate and downregulation of all inflammatory cytokines. In addition, there was upregulation of the inhibitory cytokine TGF-beta. In MBP plus LPS orally tolerized animals, in addition to upregulation of TGF-beta and reduction of inflammatory cytokines, there was enhanced expression of IL-4 and PGE2, presumably secondary to activation of an additional population of immunoregulatory cells. In OVA-fed animals that had recovered (day 18), staining for inflammatory cytokines diminished, and there was the appearance of TGF-beta and IL-4. These results suggest that suppression of EAE, either induced by oral tolerization or that which occurs during natural recovery is related to the secretion of inhibitory cytokines or factors that actively suppress the inflammatory process in the target organ.
实验性自身免疫性脑脊髓炎（EAE）在Lewis大鼠中是一种局限于中枢神经系统的自限性炎症过程，由在佐剂中注射髓鞘碱性蛋白（MBP）诱导产生。口服MBP可抑制EAE，这种抑制作用由CD8 + T细胞介导，这些细胞通过抗原特异性触发后释放转化生长因子（TGF）β来进行过继性转移保护并在体内外发挥抑制作用。此外，同时口服脂多糖（LPS）可增强对MBP的口服耐受性。本研究旨在确定EAE的病程及其通过对MBP的口服耐受诱导的抑制作用是否与靶器官中细胞因子表达的不同模式相关。在临床疾病高峰期（免疫后第14天）和恢复后（第18天），对对照（喂食卵清蛋白[OVA]）、喂食MBP和喂食MBP加LPS的动物进行详细的脑免疫组织学检查。在疾病高峰期，喂食OVA的动物的脑显示血管周围有活化的单核细胞浸润，这些细胞分泌炎性细胞因子白细胞介素（IL）1、2、6、8、肿瘤坏死因子-α（TNF-α）和干扰素γ。抑制性细胞因子TGF-β和IL-4以及前列腺素E2（PGE2）不存在。在口服耐受MBP的动物中，血管周围浸润明显减少，所有炎性细胞因子均下调。此外，抑制性细胞因子TGF-β上调。在口服耐受MBP加LPS的动物中，除了TGF-β上调和炎性细胞因子减少外，IL-4和PGE2的表达增强，推测这是由于另一群免疫调节细胞被激活所致。在恢复后的喂食OVA的动物（第18天）中，炎性细胞因子的染色减少，并且出现了TGF-β和IL-4。这些结果表明，无论是通过口服耐受诱导的EAE抑制还是自然恢复过程中发生的抑制，都与抑制性细胞因子或积极抑制靶器官中炎症过程的因子的分泌有关。
