Mj. Cameron et al., Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes, J IMMUNOL, 165(2), 2000, pp. 1102-1110
We investigated the biological role of CC chemokines in the Th1-mediated pa
thogenesis of spontaneous type I diabetes in nonobese diabetic (NOD) mice.
Whereas an elevated ratio of macrophage inflammatory protein-1 alpha (MIP-1
alpha):MIP-1 beta in the pancreas correlated with destructive insulitis an
d progression to diabetes in NOD mice, a decreased intrapancreatic MIP-1 al
pha:MIP-1 beta ratio was observed in nonobese diabetes-resistant (NOR) mice
. IL-4 treatment, which prevents diabetes in NOD mice by polarizing intrais
let Th2 responses, decreased CCR5 expression in islets and potentiated a hi
gh ratio of MIP-1 beta and monocyte chemotactic protein-1 (MCP-1): MIP-1 al
pha in the pancreas. Furthermore, NOD.MIP-1 alpha(-/-) mice exhibited reduc
ed destructive insulitis and were protected from diabetes. Neutralization o
f MIP-la with specific Abs following transfer of diabetogenic T cells delay
ed the onset of diabetes in NOD,Scid recipients. These studies illustrate t
hat the temporal expression of certain CC chemokines, particularly MIP-1 al
pha, and the CCR5 chemokine receptor in the pancreas is associated with the
development of insulitis and spontaneous type I diabetes.