title: Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Forestier
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takaki
authors.forename: Alberto
authors.initials: A
authors.lastname: Molano
authors.forename: Jin S
authors.initials: JS
authors.lastname: Im
authors.forename: Ian
authors.initials: I
authors.lastname: Baine
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Jerud
authors.forename: Petr
authors.initials: P
authors.lastname: Illarionov
authors.forename: Rachel
authors.initials: R
authors.lastname: Ndonye
authors.forename: Amy R
authors.initials: AR
authors.lastname: Howell
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Teresa P
authors.initials: TP
authors.lastname: Dilorenzo
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
mesh_terms: D000818:Animals; D018949:Antigens, CD1; D055610:Antigens, CD1d; D016207:Cytokines / Q000187:drug effects*; D003713:Dendritic Cells / Q000166:cytology; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000517:prevention & control; D005699:Galactosylceramides / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D016688:Mice, Inbred NOD; D018418:Th2 Cells / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D016207:Cytokines; D005699:Galactosylceramides; C493154:alpha-galactosylceramide