Neonatal tolerization with glutamic acid decarboxylase but not with bovine serum albumin delays the onset of diabetes in NOD mice.
To test the role of glutamic acid decarboxylase (GAD65) or bovine serum albumin (BSA) autoimmunity in the pathogenesis of diabetes, GAD65 or BSA was injected intraperitoneally into neonatal female NOD mice (100 micrograms/mouse of each protein). Treatment with GAD65, but not with BSA, significantly delayed the onset of diabetes compared with control mice (P < 0.05). At 18 weeks, 6 of 10 control mice compared with 0 of 10 GAD65-treated mice (P = 0.005) and 7 of 14 BSA-treated mice had developed diabetes. However, after 79 weeks, 6 of 10 of the GAD65-treated mice were diabetic compared with 9 of 10 of the control mice and 12 of 14 of the BSA-treated mice. In GAD65-treated mice without diabetes, insulitis was markedly reduced compared with control or BSA-treated mice (P < 10(-4)). To further elucidate why GAD becomes an autoantigen, the expression in NOD mice islets was studied. Quantitative immunohistochemistry revealed that islet cell expression of GAD was increased in 5-week-old NOD mice compared with BALB/c mice (P = 0.02). With the occurrence of insulitis (9-15 weeks), the GAD expression was further increased relative to 5-week-old NOD mice (P < 0.02). In conclusion, GAD, but not BSA, autoimmunity is important for the development of diabetes in NOD mice. Furthermore, concordant with the appearance of insulitis, the GAD expression increased in NOD mouse islets, which could possibly potentiate the beta-cell-directed autoimmunity.
Hagedorn Research Institute, Gentofte, Denmark.
J S
JS
Petersen
A E
AE
Karlsen
H
H
Markholst
A
A
Worsaae
T
T
Dyrberg
B
B
Michelsen
D000375:Aging; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000201:enzymology; D051379:Mice; D016688:Mice, Inbred NOD; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000276:immunology*
D001323:Autoantibodies; D012710:Serum Albumin, Bovine; D005968:Glutamate Decarboxylase