Escape from self-tolerance leads to neonatal insulin-dependent diabetes mellitus.
Double transgenic (dTg) mice expressing the hemagglutinin (HA) of influenza virus under the insulin promoter and the TCR specific for the immunodominant CD4 T cell epitope of HA (HA110-120) develop insulin-dependent diabetes mellitus (IDDM). In order to gain information on the breaking down of neonatal self-tolerance we studied the occurrence of IDDM after birth. Our results showed that newborn mice develop fulminant IDDM characterized by occurrence of insulitis as early as 3 days after birth, followed by hyperglycemia by 7 days, and significant hypoinsulinemia by 28 days. The neonatal breakdown of self-tolerance of T cells positively selected in the thymus is supported by the facts that: (i) peripheral HA110-120 specific T cells from neonates are fully functional and proliferated upon stimulation with the nominal peptide, and (ii) peptide-specific T cells were accumulated in the pancreas of dTg mice as early as 3 days after birth. Our results demonstrate that diabetes occurring in young dTg mice is due to early activation of self-reactive T cells immediately after birth. Accumulation of specific T cells in the target organ leads to destruction of pancreatic beta-cells and IDDM. These mice may provide a useful model to evaluate new strategies for the prevention of diabetes.
Radu
D L
DL
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Brumeanu
T D
TD
McEvoy
R C
RC
Bona
C A
CA
Casares
S
S
D000818:Animals; D000831:Animals, Newborn; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology; D051381:Rats; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology*
D019267:Hemagglutinin Glycoproteins, Influenza Virus