Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products.
Ligation of the receptor for advanced glycation end products (RAGE) occurs during inflammation. Engagement of RAGE results in enhanced expression of addressins and it is therefore, not surprising that previous studies have shown a role of RAGE/ligand interactions in immune responses including cell/cell contact but the role of RAGE in spontaneous autoimmunity has not been clearly defined. To study the role of RAGE/ligand interactions in autoimmune diabetes, we tested the ability of soluble RAGE, a scavenger of RAGE ligands, in late stages of diabetes development in the NOD mouse-disease transferred with diabetogenic T cells and recurrent disease in NOD/scid recipients of syngeneic islet transplants. RAGE expression was detected on CD4(+), CD8(+), and B cells from diabetic mice and transferred to NOD/scid recipients. RAGE and its ligand, S100B, were found in the islets of NOD/scid mice that developed diabetes. Treatment of recipient NOD/scid mice with soluble RAGE prevented transfer of diabetes and delayed recurrent disease in syngeneic islet transplants. RAGE blockade was associated with increased expression of IL-10 and TGF-beta in the islets from protected mice. RAGE blockade reduced the transfer of disease with enriched T cells, but had no effect when diabetes was transferred with the activated CD4(+) T cell clone, BDC2.5. We conclude that RAGE/ligand interactions are involved in the differentiation of T cells to a mature pathogenic phenotype during the late stages of the development of diabetes.
Chen
Yali
Y
Naomi Berrie Diabetes Center, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Yan
Shirley ShiDu
SS
Colgan
John
J
Zhang
Hui-Ping
HP
Luban
Jeremy
J
Schmidt
Ann Marie
AM
Stern
David
D
Herold
Kevan C
KC
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology; D008024:Ligands; D051379:Mice; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic