Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes.
We investigated the biological role of CC chemokines in the Th1-mediated pathogenesis of spontaneous type I diabetes in nonobese diabetic (NOD) mice. Whereas an elevated ratio of macrophage inflammatory protein-1alpha (MIP-1alpha):MIP-1beta in the pancreas correlated with destructive insulitis and progression to diabetes in NOD mice, a decreased intrapancreatic MIP-1alpha:MIP-1beta ratio was observed in nonobese diabetes-resistant (NOR) mice. IL-4 treatment, which prevents diabetes in NOD mice by polarizing intraislet Th2 responses, decreased CCR5 expression in islets and potentiated a high ratio of MIP-1beta and monocyte chemotactic protein-1 (MCP-1): MIP-1alpha in the pancreas. Furthermore, NOD.MIP-1alpha-/- mice exhibited reduced destructive insulitis and were protected from diabetes. Neutralization of MIP-1alpha with specific Abs following transfer of diabetogenic T cells delayed the onset of diabetes in NOD.Scid recipients. These studies illustrate that the temporal expression of certain CC chemokines, particularly MIP-1alpha, and the CCR5 chemokine receptor in the pancreas is associated with the development of insulitis and spontaneous type I diabetes.
Cameron
M J
MJ
Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.
Arreaza
G A
GA
Grattan
M
M
Meagher
C
C
Sharif
S
S
Burdick
M D
MD
Strieter
R M
RM
Cook
D N
DN
Delovitch
T L
TL
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D065100:CCR5 Receptor Antagonists; D002465:Cell Movement / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D005260:Female; D015847:Interleukin-4 / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010179:Pancreas / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D019713:Receptors, CCR5; D015847:Interleukin-4