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

Claire Forestier, Toshiyuki Takaki, Alberto Molano, Jin S. Im, Ian Baine, Elliot S. Jerud, Petr Illarionov, Rachel Ndonye, Amy R. Howell, Pere Santamaria, Gurdyal S. Besra, Teresa P. DiLorenzo, Steven A. Porcelli

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75 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1415-1425
Number of pages11
JournalJournal of Immunology
Volume178
Issue number3
DOIs
StatePublished - Feb 1 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Forestier, C., Takaki, T., Molano, A., Im, J. S., Baine, I., Jerud, E. S., Illarionov, P., Ndonye, R., Howell, A. R., Santamaria, P., Besra, G. S., DiLorenzo, T. P., & Porcelli, S. A. (2007). Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator. Journal of Immunology, 178(3), 1415-1425. https://doi.org/10.4049/jimmunol.178.3.1415