CCL4 protects from type 1 diabetes by altering islet beta-cell-targeted inflammatory responses.
We previously reported that interleukin (IL)-4 treatment of nonobese diabetic (NOD) mice elevates intrapancreatic CCL4 expression and protects from type 1 diabetes. Here, we show that antibody neutralization of CCL4 abrogates the ability of T-cells from IL-4-treated NOD mice to transfer protection against type 1 diabetes. Intradermal delivery of CCL4 via a plasmid vector stabilized by incorporation of the Epstein-Barr virus EBNA1/oriP episomal maintenance replicon (pHERO8100-CCL4) to NOD mice beginning at later stages of disease progression protects against type 1 diabetes. This protection was associated with a Th2-like response in the spleen and pancreas; decreased recruitment of activated CD8(+) T-cells to islets, accompanied by diminished CCR5 expression on CD8(+) T-cells; and regulatory T-cell activity in the draining pancreatic lymph nodes. Thus, inflammatory responses that target islet beta-cells are suppressed by CCL4, which implicates the use of CCL4 therapeutically to prevent type 1 diabetes.
Meagher
Craig
C
Laboratory of Autoimmune Diabetes, Robarts Research Institute, 100 Perth Drive, London, Ontario N6A 5K8, Canada.
Arreaza
Guillermo
G
Peters
Andrew
A
Strathdee
Craig A
CA
Gilbert
Philippe A
PA
Mi
Qing-Sheng
QS
Santamaria
Pere
P
Dekaban
Gregory A
GA
Delovitch
Terry L
TL
D000375:Aging; D000818:Animals; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D015316:Genetic Therapy; D007249:Inflammation / Q000517:prevention & control; D050417:Insulin-Secreting Cells / Q000473:pathology*; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
C496535:Ccl4 protein, mouse; D054407:Chemokine CCL4; D019742:Chemokines, CC; D015847:Interleukin-4