Prevention of autoimmune diabetes in the DRBB rat by CD40/154 blockade.
The autoimmune diabetes of the DRBB rat shares important similarities with autoimmune diabetes in humans. We have tested the ability of CD40/154 blockade using an anti-CD154 antibody (AH.F5) to prevent autoimmune diabetes in DRBB rats. The rats were treated with two intravenous doses/wk of AH.F5 (15mg/kg/dose) starting at 2-6wks of age. RT6.1 T-cell depletion and poly I/C was started at 4wks of age. Control rats developed diabetes within 25 days after start of depletion therapy. Six of 7, 11 of 13, 7 of 12, and 4 of 11 rats treated with AH.F5 did not develop diabetes when treatment was started at 2-3, 4, 5, and 6wks of age, respectively. The rats that did not develop diabetes were maintained for a minimum of 72 days to >150 days following the last dose of AH.F5. Eleven rats maintained for >150 days underwent an additional depletion and 5/11 developed diabetes within 8-19 days following start of depletion.Histological examination indicated that AH.F5 prevented and possibly reversed insulitis. Islets in about 50% of the treated rats remained free of inflammation following a second course of RT 6.1 T-cell depletion after the serum concentration of AH.F5 was negligible. In summary, CD40/154 blockade with AH.F5 prevents development of autoimmune diabetes if treatment is started prior to overt signs of beta cell destruction. The results indicate that the CD40/154 blockade can prevent diabetes by modifying the expansion or effector phase of the autoimmune diabetes.
Moore
Wayne V
WV
Pediatric Endocrinology, Children's Mercy Hospital, 2401 Gilham Road, Kansas City, MO 64108, USA. wmoore@cmh.edu
Chu
Wenjiang
W
Tong
Pei Y
PY
Hess
Donna
D
Benjamin
Christopher
C
Khalili
Jahan
J
Kover
Karen
K
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007275:Injections, Intravenous; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051381:Rats
D000906:Antibodies; D019013:CD40 Antigens; D023201:CD40 Ligand