Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator

C Forestier, T Takaki, A Molano, JS Im, I Baine, ES Jerud, Petr Illarionov, R Ndonye, AR Howell, P Santamaria, Gurdyal Besra, TP DiLorenzo, SA Porcelli

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Activation of CD1d-restricted invariant NKT (iNKT) cells by alpha-galactosylceramide (alphaGalCer) 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 alphaGalCer 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 alphaGalCer 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 alphaGalCer C20:2 were significantly more pronounced than those seen in direct comparisons with a closely related analog of alphaGalCer that stimulated a more mixed pattern of Th1 and Th2 cytokine secretion. Unlike a previously reported Th2-skewing murine iNKT cell agonist, the alphaGalCer C20:2 analog was strongly stimulatory for human iNKT cells and thus warrants further examination as a potential immunomodulatory agent for human disease.
Original languageEnglish
Pages (from-to)1415-1425
Number of pages11
JournalJournal of Immunology
Issue number3
Publication statusPublished - 1 Feb 2007


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