Synthetic glycolipid OCH prevents insulitis and diabetes in NOD mice

Mizuno, Miho; Masumura, Makoto; Tomi, Chiharu; Chiba, Asako; Oki, Sadaaki; Yamamura, Takashi; Miyake, Sachiko

doi:10.1016/j.jaut.2004.09.008

Cited by 81 publications

(59 citation statements)

References 34 publications

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“…Although a previous study found that repeated administration of OCH was effective for prevention of type 1 diabetes in NOD mice (12), our finding that OCH had no stimulatory activity for human iNKT cells indicated that this compound may not be suitable for development as an immunomodulator for use in humans. Given the strong activity of the C20:2 analog on human iNKT cells, it was of interest to know whether this analog would also behave as a strong iNKT cell activator and give preferential Th2-cytokine induction in NOD mice.…”

Section: Induction Of Th2-biased Cytokine Response By C20:2 In Nod Micecontrasting

confidence: 79%

“…One of the most intensively studied examples of this is an ␣GalCer analog designated OCH, in which the fatty acid chain has been shortened to C24:0 and the sphingoid base truncated to C9. This analog is a relatively selective stimulator of IL-4 secretion and has pronounced anti-inflammatory effects in NOD mice and other mouse models of autoimmune disease (6,(11)(12)(13)(14)(15). Our earlier studies identified a novel derivative of KRN7000 containing an 11,14-cisdiunsaturated C20 fatty acid (␣GalCer C20:2) as a potent iNKT cell activator that powerfully stimulates production of IL-4 in association with reduced production of IFN-␥.…”

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confidence: 99%

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Improved Outcomes in NOD Mice Treated with a Novel Th2 Cytokine-Biasing NKT Cell Activator

Forestier

Takaki

Molano

et al. 2007

The Journal of Immunology

102

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Activation of CD1d-restricted invariant NKT (iNKT) cells by α-galactosylceramide (αGalCer) significantly suppresses development of diabetes in NOD mice. The mechanisms of this protective effect are complex, involving both Th1 and Th2 cytokines and a network of regulatory cells including tolerogenic dendritic cells. In the current study, we evaluated a newly described synthetic αGalCer analog (C20:2) that elicits a Th2-biased cytokine response for its impact on disease progression and immunopathology in NOD mice. Treatment of NOD mice with αGalCer C20:2 significantly delayed and reduced the incidence of diabetes. This was associated with significant suppression of the late progression of insulitis, reduced infiltration of islets by autoreactive CD8+ T cells, and prevention of progressive disease-related changes in relative proportions of different subsets of dendritic cells in the draining pancreatic lymph nodes. Multiple favorable effects observed with αGalCer C20:2 were significantly more pronounced than those seen in direct comparisons with a closely related analog of αGalCer that stimulated a more mixed pattern of Th1 and Th2 cytokine secretion. Unlike a previously reported Th2-skewing murine iNKT cell agonist, the αGalCer C20:2 analog was strongly stimulatory for human iNKT cells and thus warrants further examination as a potential immunomodulatory agent for human disease.

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Section: Induction Of Th2-biased Cytokine Response By C20:2 In Nod Micecontrasting

confidence: 79%

mentioning

confidence: 99%

Improved Outcomes in NOD Mice Treated with a Novel Th2 Cytokine-Biasing NKT Cell Activator

Forestier

Takaki

Molano

et al. 2007

The Journal of Immunology

102

View full text Add to dashboard Cite

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“…iNKT cells are reduced in number in diabetes-prone NOD mice [4,5], and increasing the number of iNKT cells by adoptive transfer [6,7] or via the introduction of a Va14-Ja18 transgene, reduces significantly the progression of the disease [6]. A similar protection was observed after specific iNKT cell stimulation with exogenous ligands, a-galactosylceramide (a-GalCer) and its analogues [8][9][10][11]. Early reports suggested that iNKT cell protection was associated with the induction of a Th2 response to islet autoantigens [8,[10][11][12].…”

Section: Introductionmentioning

confidence: 79%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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“…Protection also often coincided with suppression of pathogenic autoreactive T and B cells, and in the generation of tolerogenic islet autoantigen specific T cells with a protective cytokine production profile [78,79]. Furthermore, treatment of mice with OCH prevented the development of diabetes and insulitis in NOD mice more profoundly than α-GalCer [82].…”

Section: Type 1 Diabetesmentioning

confidence: 98%