Islet expression of M3 uncovers a key role for chemokines in the development and recruitment of diabetogenic cells in NOD mice.
OBJECTIVE
Type 1 diabetes is an autoimmune disease characterized by a local inflammatory reaction in and around islets followed by selective destruction of insulin-secreting beta-cells. We tested the hypothesis that chemokines affect different mechanisms responsible for the development of diabetes in NOD mice.


METHODS
We examined chemokine expression in islets of NOD mice and tested their functional relevance to development of diabetes using transgenic mice expressing the mouse herpesvirus 68-encoded chemokine decoy receptor M3 (NOD-M3 mice) in insulin-secreting beta-cells.


RESULTS
Multiple chemokines were expressed in pancreatic islets of NOD mice before development of diabetes. Islet-specific expression of the pan-chemokine inhibitor M3 dramatically reduced leukocyte infiltration and islet destruction and completely blocked development of diabetes in NOD-M3 mice. M3 blocked diabetes by inhibiting the priming of diabetogenic cells in the pancreatic lymph nodes and their recruitment into the islets. This effect was specific to the pancreatic islets because M3 expression did not affect other ongoing autoimmune processes.


CONCLUSIONS
These results demonstrate that chemokines mediate afferent and efferent immunity in type 1 diabetes and suggest that broad chemokine blockade may represent a viable strategy to prevent insulitis and islet destruction.
Martin
Andrea P
AP
Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Ave., Box 1630, New York, NY 10029-6574, USA.
Grisotto
Marcos G
MG
Canasto-Chibuque
Claudia
C
Kunkel
Steven L
SL
Bromberg
Jonathan S
JS
Furtado
Glaucia C
GC
Lira
Sergio A
SA
D000818:Animals; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011401:Promoter Regions, Genetic; D051381:Rats; D019707:Receptors, Chemokine / Q000502:physiology*
D007328:Insulin; D019707:Receptors, Chemokine