Oral administration of antigens has been proposed in the prevention and treatment of autoimmune diseases. We reported that oral administration of 0.8 mg of recombinant human insulin to 6-week-old NOD mice every other day for a month generated regulatory T-cells that were able to reduce the severity of insulitis and the percentage of clinical diabetes in naive irradiated recipients when co-injected with diabetogenic T-cells. In the present study, immunohistochemical analysis of the pancreatic glands revealed that injection of T-cells from insulin-fed mice upregulated the number of interleukin (IL)-4-secreting cells within the islets. Using two strains of NOD mice congenic at the Theta, or Thyl, locus, we observed a higher proportion of T-cells from insulin-fed mice in both the spleen (7.73 ± 0.3 vs. 5.57 ± 0.2%; P < 0.001) and the pancreatic lymph nodes (10.1 ± 0.8 vs. 7.2 ± 0.7%; P < 0.05) of cotransferred mice. By reverse transcription-polymerase chain reaction (RT-PCR) analysis, mice reconstituted with T-cells from insulin-fed animals had detectable amounts of IL- 4 mRNA, specifically in the pancreatic lymph nodes (8 of 9 experimental mice vs. 1 of 9 control mice) and the pancreas (3 of 3 experimental mice vs. 0 of 3 control mice). γ-Interferon mRNA was detectable in all cotransferred animals, but IL-10 mRNA and transforming growth factor β mRNA were undetectable. These results suggested a shift from a T-helper 1 (Thl) to a Th2 pattern of cytokine expression and underlined the role of pancreatic lymph nodes in the protection. Repeated injections of 500 ug s.c. of anti-IL-4 monoclonal antibody led to an accentuation of the severity of islet infiltration and to the development of clinical diabetes. We concluded that oral administration of insulin can induce the presence of regulatory T-cells in the pancreas and the corresponding draining lymph nodes, initiate the secretion of IL-4 in this microenvironment sufficiently to suppress the activity of Thl autoreactive T-cell clones, and ultimately provide protection against autoimmune diabetes.
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Immunology and Transplantation|
January 01 1998
Protection Against Autoimmune Diabetes With Oral Insulin Is Associated With the Presence of IL-4 Type 2 T-Cells in the Pancreas and Pancreatic lymph Nodes
Corinne Ploix;
Corinne Ploix
INSERM 449, Faculty de Medecine RTH Lae'nnec
Lyon, France
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Isabelle Bergerot;
Isabelle Bergerot
INSERM 449, Faculty de Medecine RTH Lae'nnec
Lyon, France
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Nicole Fabien;
Nicole Fabien
INSERM 449, Faculty de Medecine RTH Lae'nnec
Lyon, France
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Stéphanie Perche;
Stéphanie Perche
INSERM 449, Faculty de Medecine RTH Lae'nnec
Lyon, France
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Valerie Moulin;
Valerie Moulin
INSERM 449, Faculty de Medecine RTH Lae'nnec
Lyon, France
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Charles Thivolet
Charles Thivolet
INSERM 449, Faculty de Medecine RTH Lae'nnec
Lyon, France
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Address correspondence and reprint requests to Dr. C. Thivolet, INSERM 449, Faculty de Medecine RTH Laennec, Rue Guillaume Paradin, 69372 Lyon Cedex 08, France.
Diabetes 1998;47(1):39–44
Article history
Received:
March 28 1997
Revision Received:
September 09 1997
Accepted:
September 09 1997
PubMed:
9421372
Citation
Corinne Ploix, Isabelle Bergerot, Nicole Fabien, Stéphanie Perche, Valerie Moulin, Charles Thivolet; Protection Against Autoimmune Diabetes With Oral Insulin Is Associated With the Presence of IL-4 Type 2 T-Cells in the Pancreas and Pancreatic lymph Nodes. Diabetes 1 January 1998; 47 (1): 39–44. https://doi.org/10.2337/diab.47.1.39
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