A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes
A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes
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DOI：
10.1073/pnas.94.9.4610
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发表时间：
1997-04-29
影响因子：
11.1
通讯作者：
Thivolet, C
中科院分区：
文献类型：
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作者：
Bergerot, I;Ploix, C;Thivolet, C
黏膜诱导的免疫耐受是一种用于预防或治疗因针对自身或非自身抗原的不良炎症免疫反应所导致疾病的有吸引力的策略。据报道，口服相关自身抗原和过敏原可延缓或抑制许多实验性自身免疫和过敏性疾病的临床发病。然而，这种方法通常需要长期反复给予大量耐受原，且对于已经对摄入抗原全身致敏的动物（例如已经存在自身反应性T细胞的动物，推测在患有自身免疫疾病的人类中也是如此）仅部分有效。我们最近表明，口服微克量的与霍乱毒素B亚单位（CTB）偶联的抗原能够有效抑制初免动物以及免疫动物的全身T细胞反应性。我们现在报道，喂食少量（2 - 20微克）与人胰岛素偶联的CTB能够有效抑制成年非肥胖糖尿病（NOD）小鼠的β细胞破坏和临床糖尿病。这种保护作用可通过来自CTB - 胰岛素处理动物的T细胞转移，并且与胰岛炎病变减轻相关。此外，涉及向Thy - 1.2受体注射来自同基因小鼠的致糖尿病T细胞以及来自喂食CTB - 胰岛素的同基因Thy - 1.1小鼠的T细胞的过继共转移实验表明，在胰腺周围淋巴结中选择性募集Thy - 1.1供体细胞，同时胰岛细胞浸润减少。这些结果表明，通过喂食微量的与CTB连接的胰岛细胞自身抗原可以实现对自身免疫性糖尿病的保护，并且似乎涉及保护性T细胞向引流器官损伤部位的淋巴组织的选择性迁移和滞留。
Mucosally induced immunological tolerance is an attractive strategy For preventing or treating illnesses resulting from untoward inflammatory immune reactions against self- or non-self-antigens. Oral administration of relevant autoantigens and allergens has been reported to delay or suppress onset of clinical disease in a number of experimental autoimmune and allergic disorders, However, the approach often requires repeated feeding of large amounts of tolerogens over long periods and is only partly effective in animals already systemically sensitized to the ingested antigen such as in animals already harboring autoreactive T cells, and thus presumably also in humans with an autoimmune disease, We have recently shown that oral administration of microgram amounts of antigen coupled to cholera toxin B subunit (CTB), can effectively suppress systemic T cell reactivity in naive as well as in immune animals, We nom report that feeding small amounts (2-20 mu g) of human insulin conjugated to CTB can effectively suppress beta cell destruction and clinical diabetes in adult nonobese diabetic (NOD) mice, The protective effect could be transferred by T cells from CTB-insulin-treated animals and mas associated with reduced lesions of insulitis. Furthermore, adoptive co-transfer experiments involving injection of Thy-1,2 recipients with diabetogenic T cells from syngeneic mice and T cells from congenic Thy-l,1 mice fed with CTB-insulin demonstrated a selective recruitment of Thy-1,B donor cells in the peripancreatic lymph nodes concomitant with reduced islet cell infiltration, These results suggest that protection against autoimmune diabetes can be achieved by feeding minute amounts of a pancreas islet cell autoantigen linked to CTB and appears to involve the selective migration and retention of protective T cells into lymphoid tissues draining the site of organ injury.