Preventing type 1 diabetes in late-stage pre-diabetic NOD mice with insulin: A central role for alum as adjuvant.
Preventing type 1 diabetes in late-stage pre-diabetic NOD mice with insulin: A central role for alum as adjuvant.
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DOI：
10.3389/fendo.2022.1023264
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发表时间：
2022
影响因子：
5.2
通讯作者：
Gysemans, Conny
中科院分区：
文献类型：
--
作者：
Martens, Pieter-Jan;Ellis, Darcy;Bruggeman, Ylke;Viaene, Marijke;Laureys, Jos;Teyton, Luc;Mathieu, Chantal;Gysemans, Conny
恢复对疾病相关抗原的免疫耐受是预防或阻止器官特异性自身免疫性疾病（如1型糖尿病（T1D））的一种有吸引力的方法。许多研究已经确定胰岛素是用于此类策略的关键抗原，但迄今为止，这些干预措施在人类中的成功一直不一致。抗原特异性免疫治疗的疗效可以通过优化剂量、时间和给药途径来提高，也可以通过加入明矾等佐剂来提高。本研究的目的是评估在晚期糖尿病前期给药时，明矾配制的胰岛素肽疫苗对雌性非肥胖糖尿病（NOD）小鼠预防T1D发展的效果。从10周龄开始，雌性NOD小鼠每4周皮下注射胰岛素B:8-24 （InsB:8-24）肽，以（Ins+明矾）或不含Imject®明矾（Ins）作为佐剂。糖尿病发病率被评估至30周龄。采用InsB:12-20反应性四聚体，测定血浆中胰岛素自身抗体和c肽浓度，并对胰腺引流淋巴结（PLN）和胰腺进行流式细胞术分析。与不含明矾的小鼠（71%,P < 0.05）、单独接受明矾的小鼠（76%,P < 0.01）或未治疗的小鼠（70%,P < 0.01）相比，明矾中配制的InsB:8-24肽降低了糖尿病发病率（39%）。这伴随着胰岛素严重程度的降低和c肽的保存。Ins+明矾与胰腺中致病效应记忆CD4+和CD8+ T细胞的频率降低以及PLN中胰岛素反应性FoxP3+ Tregs的频率增加有关。有趣的是，胰岛素反应性treg在表达FoxP3稳定表达和增强抑制功能标记的treg群体中富集。InsB:8-24肽疫苗可预防晚期糖尿病前期NOD小鼠的T1D发病，但仅在明矾中配制。这些发现支持在未来的试验中使用明矾作为佐剂来优化抗原特异性免疫治疗的疗效。
Restoration of immune tolerance to disease-relevant antigens is an appealing approach to prevent or arrest an organ-specific autoimmune disease like type 1 diabetes (T1D). Numerous studies have identified insulin as a key antigen of interest to use in such strategies, but to date, the success of these interventions in humans has been inconsistent. The efficacy of antigen-specific immunotherapy may be enhanced by optimising the dose, timing, and route of administration, and perhaps by the inclusion of adjuvants like alum. The aim of our study was to evaluate the effect of an insulin peptide vaccine formulated with alum to prevent T1D development in female non-obese diabetic (NOD) mice when administered during late-stage pre-diabetes. Starting at 10 weeks of age, female NOD mice received four weekly subcutaneous injections of an insulin B:8-24 (InsB:8-24) peptide with (Ins+alum) or without Imject® alum (Ins) as adjuvant. Diabetes incidence was assessed for up to 30 weeks of age. Insulin autoantibodies and C-peptide concentrations were measured in plasma and flow cytometric analysis was performed on pancreatic-draining lymph nodes (PLN) and pancreas using an InsB:12-20-reactive tetramer. InsB:8-24 peptide formulated in alum reduced diabetes incidence (39%), compared to mice receiving the InsB:8-24 peptide without alum (71%, P < 0.05), mice receiving alum alone (76%, P < 0.01), or mice left untreated (70%, P < 0.01). This was accompanied by reduced insulitis severity, and preservation of C-peptide. Ins+alum was associated with reduced frequencies of pathogenic effector memory CD4+ and CD8+ T cells in the pancreas and increased frequencies of insulin-reactive FoxP3+ Tregs in the PLN. Of interest, insulin-reactive Tregs were enriched amongst populations of Tregs expressing markers indicative of stable FoxP3 expression and enhanced suppressive function. An InsB:8-24 peptide vaccine prevented the onset of T1D in late-stage pre-diabetic NOD mice, but only when formulated in alum. These findings support the use of alum as adjuvant to optimise the efficacy of antigen-specific immunotherapy in future trials.
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影响因子：
7.3
作者：
通讯作者：
--
影响因子：
3
作者：
Agardh, CD;Cilio, CM;Lernmark, Å
通讯作者：
Lernmark, Å
影响因子：
120.7
作者：
Bonifacio, Ezio;Ziegler, Anette-G.;Achenbach, Peter
通讯作者：
Achenbach, Peter
影响因子：
158.5
作者：
Ludvigsson, Johnny;Faresjo, Maria;Casas, Rosaura
通讯作者：
Casas, Rosaura
DOI：
10.4049/jimmunol.1000108
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ernst PB;Garrison JC;Thompson LF
通讯作者：
Thompson LF