Oral administration of human insulin to NOD mice generates CD4+ T cells that suppress adoptive transfer of diabetes.
Oral administration of porcine insulin has been shown to be effective in preventing the spontaneous occurrence of diabetes in the Non-Obese Diabetic (NOD) mouse model. In the present study, we demonstrate that feeding 6-week-old female mice with 20 units of human insulin every 2-3 days for 30 days induces an active mechanism of suppression through the generation of regulatory T cells. Adult irradiated NOD males i.v. injected with 5 x 10(6) T cells from the spleens of diabetic female donors and the same number of T cells from the spleens of insulin-fed animals had less successful diabetes transfer than controls (4/15 vs. 8/16, P < 0.001). Protection from clinical diabetes was associated with a reduction in severe insulitis (16.4 +/- 3.6% vs. 52.3 +/- 12.8%, P = 0.023). However, more than 85% of the islets were inflamed. Feeding animals for 15 days reduced the magnitude of this protection since the number of successful transfers after 1 month was comparable (12/17 vs. 14/17) despite a significant delay in diabetes onset (P < 0.001). No difference in the contribution of T cell subsets was noted by cytofluorometry in the spleens of treated animals. When T cell subsets from insulin-fed animals were co-injected with diabetogenic T cells, only purified CD4+ T cells were able to transfer protection since only 3/12 mice became diabetic after 36 days in comparison to 3/6 in the group co-injected with CD4+ T cells from PBS-fed animals, or 5/6 in the group injected with CD8+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
INSERM U. 197, Faculté de Médecine Alexis Carrel, Lyon, France.
I
I
Bergerot
N
N
Fabien
V
V
Maguer
C
C
Thivolet
D000818:Animals; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000473:pathology; D007519:Isoantigens / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D013045:Species Specificity; D013154:Spleen; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*
D007328:Insulin; D007519:Isoantigens