Insulin B-chain reactive CD4+ regulatory T-cells induced by oral insulin treatment protect from type 1 diabetes by blocking the cytokine secretion and pancreatic infiltration of diabetogenic effector T-cells.
The mechanism of protection from type 1 diabetes conferred by regulatory T-cells induced by oral insulin treatment of NOD mice is not well understood. We demonstrate that oral insulin feeding of NOD mice induces the function of insulin B-chain reactive CD4+ regulatory T-cells, which compete with diabetogenic effector T-cells for the recognition of insulin in NOD.Scid recipient mice. These effector T-cells become deprived of interleukin (IL)-2 and interferon (IFN)-gamma and are unable to expand and migrate to the pancreas. Type 1 diabetes-protective splenic regulatory T-cells secrete relatively little transforming growth factor (TGF)-beta1, suggesting that TGF-beta may not contribute to the inactivation of effector T-cells in NOD.Scid recipients. The observed preferential infiltration of insulin-reactive regulatory T-cells rather than effector T-cells in the pancreas results in a nondestructive insulitis that correlates with an increased intrapancreatic expression of macrophage inflammatory protein-1beta. Thus, oral insulin therapy overcomes a deficiency in regulatory T-cells and protects against type 1 diabetes by inducing insulin B-chain reactive regulatory T-cells to block cytokine secretion and migration of diabetogenic effector T-cells to the pancreas. Our data emphasize that continuous oral insulin feeding over a prolonged period is required to prevent type 1 diabetes.
Bergerot
I
I
Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.
Arreaza
G A
GA
Cameron
M J
MJ
Burdick
M D
MD
Strieter
R M
RM
Chensue
S W
SW
Chakrabarti
S
S
Delovitch
T L
TL
D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D007328:Insulin / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments