Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice

被引:21
作者
Blumenfeld, H. J. [1 ,2 ]
Tohn, R. [1 ,2 ]
Haeryfar, S. M. M. [2 ]
Liu, Y. [3 ]
Savage, P. B. [3 ]
Delovitch, T. L. [1 ,2 ]
机构
[1] Univ Western Ontario, Robarts Res Inst, Lab Autoimmune Diabet, London, ON N6A 5K8, Canada
[2] Univ Western Ontario, Dept Microbiol & Immunol, London, ON N6A 5K8, Canada
[3] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA
基金
加拿大健康研究院;
关键词
dendritic cells; glycolipid agonist; immunoregulation; iNK T cells; Type; 1; diabetes; LIGAND ALPHA-GALACTOSYLCERAMIDE; NKT CELLS; DENDRITIC CELLS; NOD MICE; HUMAN CD1D; LYMPH-NODES; INKT CELLS; ACTIVATION; IMMUNITY; PREVENTS;
D O I
10.1111/j.1365-2249.2011.04454.x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Because invariant natural killer T (iNK T) cells link innate and adaptive immunity, the structure-dependent design of iNK T cell agonists may have therapeutic value as vaccines for many indications, including autoimmune disease. Previously, we showed that treatment of non-obese diabetic (NOD) mice with the iNK T cell activating prototypic glycolipid alpha-galactosylceramide (alpha-GalCer) protects them from type 1 diabetes (T1D). However, alpha-GalCer is a strong agonist that can hyperactivate iNK T cells, elicit several side effects and has shown only limited success in clinical trials. Here, we used a structure-guided design approach to identify an iNK T cell agonist that optimally protects from T1D with minimal side effects. Analyses of the kinetics and function of a panel of synthetic alpha-GalCer fatty acyl chain derivatives (C8:0-C16:0) were performed in NOD mice. C16:0 elicited the highest protection from insulitis and T1D, which was associated with a higher frequency and survival of iNK T cells and enhanced activity of tolerogenic dendritic cells (DCs) in draining pancreatic lymph nodes (PLN), inability to transactivate NK cells and a more rapid kinetics of induction and recovery of iNK T cells from anergy. We conclude that the length and structure of the acyl chain of alpha-GalCer regulates the level of protection against T1D in mice, and propose that the extent of this protection depends on the relative capacity of the acyl chain to accommodate an endogenous spacer lipid of appropriate length and structure. Thus, our findings with the alpha-GalCer C16:0 derivative suggest strongly that it be considered as a lead glycolipid candidate in clinical trials of T1D.
引用
收藏
页码:121 / 133
页数:13
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