Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator.
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.
Forestier
Claire
C
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Takaki
Toshiyuki
T
Molano
Alberto
A
Im
Jin S
JS
Baine
Ian
I
Jerud
Elliot S
ES
Illarionov
Petr
P
Ndonye
Rachel
R
Howell
Amy R
AR
Santamaria
Pere
P
Besra
Gurdyal S
GS
Dilorenzo
Teresa P
TP
Porcelli
Steven A
SA
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
D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D016207:Cytokines; D005699:Galactosylceramides; C493154:alpha-galactosylceramide