Premium
Regulatory Natural Killer T Cells Protect against Spontaneous and Recurrent Type 1 Diabetes
Author(s) -
SHARIF SHAYAN,
ARREAZA GUILLERMO A.,
ZUCKER PETER,
DELOVITCH TERRY L.
Publication year - 2002
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2002.tb02949.x
Subject(s) - nod , natural killer t cell , immunology , nod mice , type 1 diabetes , immune system , cyclophosphamide , autoimmunity , medicine , biology , cancer research , endocrinology , diabetes mellitus , t cell , chemotherapy
A bstract : Autoimmune diseases, especially type 1 diabetes (T1D), may be caused by dysregulation of the immune system, which leads to hyporesponsiveness of regulatory T helper 2 (Th2) cells and promotion of autoimmune Th1 cells. Natural killer T (NKT) cells, which comprise a minor subpopulation of T cells, play a critical role in immunoregulation as a result of a rapid burst of IL‐4 and IFN‐γ secretion. These cells are functionally and numerically deficient in individuals at risk of T1D, as well as in nonobese diabetic (NOD) mice. It is conceivable that protection from T1D may be achieved by correction of this deficiency. Alpha‐galactosylceramide (α‐GalCer) specifically binds to NKT cells in a CD1‐dependent manner and stimulates these cells to proliferate and to produce various cytokines, including IFN‐γ, IL‐4, and IL‐10. In this review, we present evidence that a multiple‐dose α‐GalCer treatment regimen, which is known to promote a dominant Th2 environment, can prevent the onset of spontaneous and cyclophosphamide (CY)‐accelerated T1D. This protection is associated with elevated IL‐4 and IL‐10 in the spleen and pancreas of protected female NOD mice. Concomitantly, IFN‐γ levels are reduced in both tissues. More importantly, the protective effect of γ‐GalCer in CY‐accelerated T1D is abrogated by the in vivo blockade of IL‐10 activity. We also show that α‐GalCer treatment significantly prolongs syngeneic islet graft survival in recipient diabetic NOD mice. These findings raise the possibility that α‐GalCer treatment may be used therapeutically to prevent the onset and recurrence of human T1D.