Cowden W B, Cullen F A, Staykova M A, Willenborg D O
Division of Immunology and Cell Biology, The John Curtin School of Medical Research, The Australian National University, Canberra ACT.
J Neuroimmunol. 1998 Aug 1;88(1-2):1-8. doi: 10.1016/s0165-5728(98)00040-x.
Rat strains vary in their susceptibility to experimental autoimmune encephalomyelitis (EAE) and in many cases, factors other than MHC antigens are thought to play a role in this. We found that PVG rats, which have a very low susceptibility to EAE, were rendered highly susceptible to clinical disease when treated with N-methylarginine (NMA) an inhibitor of nitric oxide synthase (NOS). The clinical course of the ensuing disease in NMA-treated PVG rats was in most cases fulminating in nature and accompanied by some mortality. Following immunisation with myelin basic protein (MBP)-complete Freund's adjuvant (CFA), PVG rats developed higher serum levels of the surrogate markers of nitric oxide production, reactive nitrogen intermediates (RNI; nitrite and nitrate), than did their Lewis counterparts. This in vivo finding was reflected in vitro, where the levels of RNI produced in 24, 48 and 72 h IFN-gamma-stimulated spleen cell cultures for PVG rats were significantly higher than those for Lewis rats. A mechanism by which increased NO production might protect PVG rats against clinical EAE was suggested by the finding that lymph node cells, isolated from NMA-treated MBP-immunised PVG rats, proliferated in response to MBP at a rate approximately 3 x greater than those from MBP-immunised, saline treated rats. Thus, the greater number of MBP-specific T cells generated in the NOS inhibitor-treated vs. untreated rats could account for their increased susceptibility to developing clinical EAE. The findings in this study suggest that NO plays a role in protecting PVG rats against developing EAE.
大鼠品系对实验性自身免疫性脑脊髓炎（EAE）的易感性各不相同，在许多情况下，人们认为主要组织相容性复合体（MHC）抗原以外的因素在其中发挥作用。我们发现，对EAE易感性极低的PVG大鼠在用一氧化氮合酶（NOS）抑制剂N - 甲基精氨酸（NMA）处理后，对临床疾病变得高度易感。在大多数情况下，NMA处理的PVG大鼠随后发生的疾病临床过程极为严重，并伴有一定死亡率。用髓鞘碱性蛋白（MBP）-完全弗氏佐剂（CFA）免疫后，PVG大鼠血清中一氧化氮产生的替代标志物——活性氮中间体（RNI；亚硝酸盐和硝酸盐）的水平高于Lewis大鼠。这一体内发现也反映在体外实验中，PVG大鼠经24、48和72小时干扰素 - γ刺激的脾细胞培养物中产生的RNI水平显著高于Lewis大鼠。从NMA处理的MBP免疫的PVG大鼠分离的淋巴结细胞对MBP的增殖反应速率比MBP免疫的生理盐水处理大鼠快约3倍，这一发现提示了一氧化氮产生增加可能保护PVG大鼠免受临床EAE侵害的机制。因此，与未处理大鼠相比，经NOS抑制剂处理的大鼠产生的MBP特异性T细胞数量更多，这可能是它们对临床EAE易感性增加的原因。本研究结果表明，一氧化氮在保护PVG大鼠免受EAE侵害中发挥作用。
