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Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.

Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H - J. Exp. Med. (2003)

Bottom Line: Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed.Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display.In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in beta cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

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Cells mediating GAD65-specific tolerance. (A) NOD mice were lethally irradiated and reconstituted with bone marrow from NOD (open bars) or GAD65tg. mice (gray bars). Proliferative recall responses after immunization with GAD65. CF, culture filtrate protein of M. tuberculosis as positive control. Representative result out of three independent experiments. (B) Thymectomized NOD mice were engrafted with E14 fetal thymi from NOD (open bars) or GAD65tg. mice (gray bars) and, after ablative irradiation, reconstituted with NOD bone marrow. Proliferative recall responses after immunization with GAD65.
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fig4: Cells mediating GAD65-specific tolerance. (A) NOD mice were lethally irradiated and reconstituted with bone marrow from NOD (open bars) or GAD65tg. mice (gray bars). Proliferative recall responses after immunization with GAD65. CF, culture filtrate protein of M. tuberculosis as positive control. Representative result out of three independent experiments. (B) Thymectomized NOD mice were engrafted with E14 fetal thymi from NOD (open bars) or GAD65tg. mice (gray bars) and, after ablative irradiation, reconstituted with NOD bone marrow. Proliferative recall responses after immunization with GAD65.

Mentions: As all MHC class II–positive APC can express the modified form of GAD65 it was of interest to dissect the respective roles of hematopoietic APC versus thymic epithelial cells for tolerance induction. Transplantation of GAD65tg. bone marrow into irradiated NOD mice resulted in GAD65-specific tolerance indicating that expression by hematopoietic cells was sufficient for tolerance induction (Fig. 4 A). Likewise, transplantation of irradiated GAD65tg E14 fetal thymi into NOD mice and subsequent reconstitution with nontransgenic bone marrow resulted in GAD-specific tolerance (Fig. 4 B). This indicates that GAD expression by thymic epithelial cells suffices to induce tolerance in developing T cells.


Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.

Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H - J. Exp. Med. (2003)

Cells mediating GAD65-specific tolerance. (A) NOD mice were lethally irradiated and reconstituted with bone marrow from NOD (open bars) or GAD65tg. mice (gray bars). Proliferative recall responses after immunization with GAD65. CF, culture filtrate protein of M. tuberculosis as positive control. Representative result out of three independent experiments. (B) Thymectomized NOD mice were engrafted with E14 fetal thymi from NOD (open bars) or GAD65tg. mice (gray bars) and, after ablative irradiation, reconstituted with NOD bone marrow. Proliferative recall responses after immunization with GAD65.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193961&req=5

fig4: Cells mediating GAD65-specific tolerance. (A) NOD mice were lethally irradiated and reconstituted with bone marrow from NOD (open bars) or GAD65tg. mice (gray bars). Proliferative recall responses after immunization with GAD65. CF, culture filtrate protein of M. tuberculosis as positive control. Representative result out of three independent experiments. (B) Thymectomized NOD mice were engrafted with E14 fetal thymi from NOD (open bars) or GAD65tg. mice (gray bars) and, after ablative irradiation, reconstituted with NOD bone marrow. Proliferative recall responses after immunization with GAD65.
Mentions: As all MHC class II–positive APC can express the modified form of GAD65 it was of interest to dissect the respective roles of hematopoietic APC versus thymic epithelial cells for tolerance induction. Transplantation of GAD65tg. bone marrow into irradiated NOD mice resulted in GAD65-specific tolerance indicating that expression by hematopoietic cells was sufficient for tolerance induction (Fig. 4 A). Likewise, transplantation of irradiated GAD65tg E14 fetal thymi into NOD mice and subsequent reconstitution with nontransgenic bone marrow resulted in GAD-specific tolerance (Fig. 4 B). This indicates that GAD expression by thymic epithelial cells suffices to induce tolerance in developing T cells.

Bottom Line: Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed.Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display.In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in beta cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

Show MeSH
Related in: MedlinePlus