Effects of insulin like growth factor-1 and insulin on effector T cells generating autoimmune diabetes.
To compare the protective effects of IGF-1 and insulin on the autoimmune process of beta-cell destruction, permissive NOD recipients were adoptively transferred with 7 x 10(6) autoreactive T cells from diabetic NOD mice and then administered either 10 micrograms of rhIGF-1 or 0.5 unit of regular insulin subcutaneously twice daily for three weeks. The final incidence of successful transfers of diabetes observed at day 22 was significantly reduced in 1/12 mice (8.3%) treated with IGF-1, while diabetes was observed in 4/10 (40%) receiving insulin and 7/11 (63.4%) controls. A marked reduction of insulitis during histological analysis of the pancreatic glands of IGF-1 or insulin-treated mice was also observed. Non-diabetic mice treated with rhIGF-1 had a higher mean +/- SD percentage of intact islets (68.9 +/- 36% vs 10.7 +/- 13%, p < 0.01) and a lower percentage of severely infiltrated islets (5.7 +/- 9.8% vs 30.3 +/- 21%) than non-diabetic control mice. Insulin reduced islet-cell infiltration, though to a lesser extent, with a high percentage of normal islets (55.2 +/- 31%, p < 0.02). Some mice developed diabetes and severe islet-cell infiltration despite rhIGF-1 or insulin, thus indicating that some committed T cells were still able to invade islets and cause beta-cell destruction. To evaluate the effects of rhIGF-1 and insulin on cell trafficking in recipient mice, T cells from diabetic NOD Thy-1, 2 mice injected into congenic NOD-N Thy-1, 1 mice were monitored three weeks after adoptive cell transfer. The percentage of Thyq-1.2+ T cells was significantly reduced in the spleen (10.8 +/- 1.3% vs 17.2 +/- 3.9%, p = 0.004) of rhIGF-1 treated mice as compared to the thymus (68.4 +/- 7.9% vs 72.87 +/0 6.2, p = 0.306). Similar experiments performed in mice treated with insulin revealed no significant differences in the percentages of Thy-1,2+ T cells compared to controls in the spleen (l4.3 +/- 1.4%), thymus (84 +/- 2.5%) or pancreatic lymph nodes (21.5 +/- 1.6% vs 23.4 +/- 1.5%) of treated animals. These results suggest that rhIGF-1, as compared to insulin, could influence T-cell trafficking to the lymphoid organs in addition to affecting beta cells. These findings may have important implications for new preventive strategies in human Type 1 diabetes mellitus.
Bergerot
I
I
INSERM U. 448, Faculté de Médecine, RTH Laënnec, Lyon, France.
Fabien
N
N
Thivolet
C
C
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive; D007279:Injections, Subcutaneous; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D011994:Recombinant Proteins / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
D007004:Hypoglycemic Agents; D007328:Insulin; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I