title: NKT cell defects in NOD mice suggest therapeutic opportunities.
abstract: Recent studies have reported that immunoregulatory NKT cells are defective in NOD mice and that treatment of mice with alpha-galactosylceramide that selectively stimulate NKT cells, is anti-diabetogenic. The objective of this study was to document the natural history of changes in NKT cells in various organs in NOD mice in the period up to the time of diabetes onset so that novel intervention therapies could be devised. We found that NKT cell-specific receptor (NKT-TCR) Valpha14Jalpha281 expressions by quantitative (RealTime) RT-PCR in thymus, spleen and liver of NOD male and female mice were low at 1-3 months of life compared to BALB/c and C57BL/6 mice, albeit a transient spike in levels occurred in female NOD livers at 2 months. Female pancreases showed low levels of these transcripts despite their active and destructive insulitis. In contrast, NOD males exhibited high expression of this invariant TCR in pancreas, where their insulitis was less destructive. A survey of NKT-TCR expressions in a battery of congenic, non-diabetes prone NOD strains indicated that this NKT phenotype was quite variable but higher than diabetes prone NOD. Bone marrow transplantation of NOD females from B6.NOD-H2(g7) donors raised their NKT-TCR expressions. Tuberculin administrations in the forms of BCG and CFA in a manner known to protect NOD mice from diabetes both raised NKT-TCR levels, as did the anti-inflammatory PPAR-gamma agonist rosiglitazone. These findings provide exciting therapeutic avenues to be explored in the treatment of human immune mediated type-1 diabetes where there are similar immunoregulatory lesions.
authors.affiliation: Department of Pediatrics, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Anjli
authors.initials: A
authors.lastname: Kukreja
authors.forename: Guilia
authors.initials: G
authors.lastname: Costi
authors.forename: John
authors.initials: J
authors.lastname: Marker
authors.forename: Chen Hui
authors.initials: CH
authors.lastname: Zhang
authors.forename: Sunil
authors.initials: S
authors.lastname: Sinha
authors.forename: Zhong
authors.initials: Z
authors.lastname: Sun
authors.forename: Noel
authors.initials: N
authors.lastname: Maclaren
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009928:Organ Specificity / Q000276:immunology
chemical_list: D018949:Antigens, CD1; D016169:Lymphocyte Function-Associated Antigen-1