Three‐year Open Protocol Continuation Study of Oral Tolerization with Myelin Antigens in Multiple Sclerosis and Design of a Phase III Pivotal Trial
Three‐year Open Protocol Continuation Study of Oral Tolerization with Myelin Antigens in Multiple Sclerosis and Design of a Phase III Pivotal Trial
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多发性硬化症中髓磷脂抗原口服耐受的三年开放方案持续研究和 III 期关键试验的设计
DOI：
10.1111/j.1749-6632.1996.tb21132.x
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发表时间：
1996
影响因子：
5.2
通讯作者：
H. Weiner
中科院分区：
文献类型：
--
作者：
M. Hohol;S. Khoury;Sandra L Cook;E. Orav;D. Hafler;H. Weiner
多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症性疾病，推测其自身免疫性病因。直到最近，大多数治疗方法都使用具有固有毒性的非特异性免疫抑制药物，这往往限制了它们的使用，特别是在疾病病程的早期，这是治疗最有可能证明有益的时候。较新的策略包括更特异性的免疫调节药物，如干扰素- β和共聚物-1，它们在大型多中心临床试验中已被证明对病程有积极作用。2.3然而，这些药物需要肠外给药，并不是没有副作用。口服耐受是一种通过口服抗原诱导特异性免疫低反应性的方法。这个概念多年来得到了广泛认可。1911年，Wells发现给豚鼠喂食鸡蛋蛋白可以抑制对相同物质的全身过敏反应口服耐受性的进化可能是为了防止对摄入的营养和生存所必需的蛋白质的全身免疫反应。口服抗原会遇到肠道相关淋巴组织（GALT），这是一个发育良好的免疫网络，由绒毛组成，绒毛中含有能够递呈抗原的上皮细胞，上皮内淋巴细胞和固有层，这些细胞是由肠道相关淋巴组织形成的。此外，绒毛下面散布着淋巴样结节，称为Peyer's斑块，是GALT的主要区域之一，在那里产生特异性免疫反应。低剂量的口服抗原通过产生活性细胞抑制来实现口服耐受，活性细胞抑制是通过诱导GALT中的调节性T细胞介导的。这些T细胞在靶器官微环境中遇到口服耐受原时，会分泌抑制性细胞因子（如转化生长因子P （TGF-P）、il - 4和IL-10）。口服髓鞘碱性蛋白（MBP）可抑制急性实验性自身免疫性脑脊髓炎（EAE9.6）和慢性复发性脑脊髓炎（EAE），发病后口服MBP或髓鞘可抑制EAE。理论上，口服耐受性可能不需要知道自身免疫反应所针对的自身抗原，只要它是一种能够诱导调节的抗原
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) of presumed autoimmune etiology. Until recently, most therapeutic approaches have involved nonspecific immunosuppressive drugs with inherent toxicities, which often limit their use, especially early in the disease course, a time when therapy is most Likely to prove beneficial.' Newer strategies include more specific immunomodulatory drugs, such as interferon-beta and copolymer-1, which have been shown, in large multicenter clinical trials, to have a positive effect on the disease course.2.3 However, these drugs require parenteral administration and are not without adverse effects. Oral tolerization is a method of inducing specific immunologic hyporesponsiveness through oral administration of antigen. The concept has been well recognized for many years. In 191 1, Wells showed that feeding hen egg protein to guinea pigs inhibited systemic anaphylaxis to the same material.4 Oral tolerance presumably evolved to prevent systemic immune reactions to ingested proteins necessary for nutrition and thus survival. Orally administered antigen encounters gut-associated lymphoid tissue (GALT), a well-developed immune network, consisting of villi that contain epithelial cells capable of antigen presentation, intraepithelial lymphocytes, and lamina propria l y m p h ~ y t e s . ~ In addition, there are lymphoid nodules, known as Peyer's patches, interspersed below the villi, which are one of the primary areas in the GALT, where specific immune responses are generated. Low doses of oral antigen achieve oral tolerance by way of generation of active cellular suppression, which is mediated by the induction of regulatory T cells in the GALT. These T cells secrete suppressive cytokines (such as transforming growth factor P (TGF-P), IL4, and IL-10) when they encounter the oral tolerogen in the microenvironment of the target organ. Oral administration of myelin basic protein (MBP) suppresses acute experimental autoimmune encephalomyelitis (EAE9.6' and chronic, relapsing EAE can be suppressed after the onset of disease by oral administration of MBP or myelin.' Theoretically, one may not need to known the autoantigen against which the autoimmune response is directed for oral tolerance to be effective as long as it is an antigen capable of inducing regulatory
DOI：
10.1073/pnas.88.22.10252
发表时间：
1991-11-01
影响因子：
11.1
作者：
ZHANG, ZJ;DAVIDSON, L;WEINER, HL
通讯作者：
WEINER, HL
DOI：
10.1073/pnas.83.19.7443
发表时间：
1986-10-01
影响因子：
11.1
作者：
NAGLERANDERSON, C;BOBER, LA;THORBECKE, GJ
通讯作者：
THORBECKE, GJ
影响因子：
56.9
作者：
WEINER, HL;MACKIN, GA;HAFLER, DA
通讯作者：
HAFLER, DA