CONTROL OF ESTABLISHED EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS BY INHIBITION OF TUMOR-NECROSIS-FACTOR (TNF) ACTIVITY WITHIN THE CENTRAL-NERVOUS-SYSTEM USING MONOCLONAL-ANTIBODIES AND TNF RECEPTOR IMMUNOGLOBULIN FUSION PROTEINS
CONTROL OF ESTABLISHED EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS BY INHIBITION OF TUMOR-NECROSIS-FACTOR (TNF) ACTIVITY WITHIN THE CENTRAL-NERVOUS-SYSTEM USING MONOCLONAL-ANTIBODIES AND TNF RECEPTOR IMMUNOGLOBULIN FUSION PROTEINS
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DOI：
10.1002/eji.1830240916
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发表时间：
1994-09-01
影响因子：
5.4
通讯作者：
FELDMANN, M
中科院分区：
文献类型：
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作者：
BAKER, D;BUTLER, D;FELDMANN, M
在Biozzi AB/H小鼠主动诱导、慢性复发性实验性变态反应性脑脊髓炎(CREAE)的发展过程中，使用小鼠肿瘤坏死因子特异性抗体(TN3.19.12)和双价人p55和p75肿瘤坏死因子受体-免疫球蛋白融合蛋白(TNFR-Ig)，抑制肿瘤坏死因子活性。如果在预期发病之前反复给予抗体剂量，可以抑制疾病的发展。现在还表明，即使在临床症状出现后给予抗体，治疗效果也是明显的，进一步表明肿瘤坏死因子在CREAE的致病效应机制中发挥了重要作用。虽然在循环中没有检测到具有生物活性的肿瘤坏死因子，但在中枢神经系统(CNS)内的病变中检测到了肿瘤坏死因子-α。这表明中枢神经系统可能是肿瘤坏死因子特异性免疫调节的主要部位，并得到了颅内注射对抗体和TNFR-Ig融合蛋白的效力明显高于全身注射的观察结果的支持。当融合蛋白的剂量比抗体的剂量低10-100倍时，融合蛋白的效价与抗体相同，反映了它们较高的体外中和能力。虽然治疗不是治愈的，如果不持续治疗，这种模型不可避免地会复发，但数据表明，抗肿瘤坏死因子免疫治疗，特别是在中枢神经系统内，可以抑制CREAE，因此，可能有助于控制人类神经免疫性疾病。
Tumor necrosis factor (TNF) activity was inhibited during the development of actively-induced, chronic relapsing experimental allergic encephalomyelitis (CREAE) in Biozzi AB/H mice, using a mouse TNF-specific (TN3.19.12) antibody and bivalent human p55 and p75 TNF receptor-immunoglobulin (TNFR-Ig) fusion proteins. The development of disease could be inhibited when repeated doses of antibody were administered prior to the anticipated onset. It has now also been shown that a therapeutic effect is evident even when antibody is administered after the onset of clinical signs, further indicating an important role for TNF in pathogenic effector mechanisms in CREAE. Although biologically-active TNF was not detected in the circulation, TNF-alpha was detected in lesions within the central nervous system (CNS). This suggested that the CNS may be the main site for TNF-specific immunomodulation and was supported by the observation that intracranial injection was significantly more potent than that administered systemically, for both antibody and TNFR-Ig fusion proteins. The fusion proteins were as effective as antibody at doses 10-100-fold lower than that used for antibody, reflecting their higher neutralizing capacity in vitro. Although treatment was not curative and relapse inevitably occurred in this model if treatment was not sustained, the data indicate that anti-TNF immunotherapy, especially within the CNS, can inhibit CREAE and may, therefore, be useful in the control of human neuroimmunological diseases.