Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4+ regulatory T-cells
Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4+ regulatory T-cells. C Ploix , I Bergerot , A Durand , C Czerkinsky , J Holmgren and C Thivolet Faculté de Médecine RTH Laennec, Lyon, France. Abstract Restoration of peripheral toler...
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Published in | Diabetes (New York, N.Y.) Vol. 48; no. 11; pp. 2150 - 2156 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.11.1999
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Subjects | |
Online Access | Get full text |
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Summary: | Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4+ regulatory
T-cells.
C Ploix ,
I Bergerot ,
A Durand ,
C Czerkinsky ,
J Holmgren and
C Thivolet
Faculté de Médecine RTH Laennec, Lyon, France.
Abstract
Restoration of peripheral tolerance to target autoantigens during autoimmune diseases has met with several limitations because
of the limited efficacy of this approach in an already immune host. To optimize the induction of tolerance, we have shown
that feeding insulin conjugated to cholera toxin B-subunit (CTB), a potent mucosal adjuvant, reduced by 5,000 the amounts
of antigen necessary for delaying diabetes onset in NOD mice. To analyze these protective mechanisms, we have performed cotransfer
experiments using splenocytes from young females fed once with 10 microg of CTB-insulin, mixed with diabetogenic T-cells,
and intravenously injected into irradiated syngeneic male recipients. We demonstrated that the delayed onset of diabetes relied
on CD4+ T-cells. We studied the cytokine production from plate-bound anti-CD3-stimulated cells. Higher interleukin (IL)-4
amounts were observed in both splenocytes and pancreatic lymph node (PLN) cell cultures from CTB-insulin-fed mice as soon
as 4 h after the feeding. An increase in the levels of transforming growth factor-beta was seen after 24 h only in the mesenteric
lymph nodes (MLN). In both of these organs, a reduction of gamma-interferon (IFN-gamma) production occurred after CTB-insulin
treatment, at 24 h in the PLN and at 7 days in the MLN. Reverse transcription-polymerase chain reaction analysis indicated
an increase in the level of IL-4 and a reduction in IFN-gamma transcripts in the PLN of mice treated orally with CTB-insulin
and of the recipients of regulatory T-cells. Using different strains of congenic NOD mice at the Thy1 locus, we showed that
protection was associated with the accumulation of T-cells from CTB-insulin-fed mice in the lymph nodes from draining sites
containing functional islets, i.e., the PLN in normal mice and the renal lymph nodes after a syngeneic islet graft under the
kidney capsule of streptozotocin-treated mice. Taken together, our results clearly indicate that oral administration of CTB-insulin
conjugates in NOD mice produced a shift from a T-helper type 1 to a type 2 profile with the induction of antigen-specific
regulatory CD4+ T-cells in the vicinity of the mucosal barrier and close to the inflamed islets. |
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ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.48.11.2150 |