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Pancreatic lymph nodes are required for priming of beta cell reactive T cells in NOD mice.

Gagnerault MC, Luan JJ, Lotton C, Lepault F - J. Exp. Med. (2002)

Bottom Line: The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells.In contrast, splenectomy had no effect at any age.Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did.

View Article: PubMed Central - PubMed

Affiliation: Centre National de la Recherche Scientifique Unité Mixte de Recherche 8603, Université René Descartes, Hôpital Necker, 75015 Paris, France.

ABSTRACT
Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that results from the destruction of insulin secreting beta cells by diabetogenic T cells. The time and location of the encounter of autoantigen(s) by naive autoreactive T cells in normal NOD mice are still elusive. To address these issues, we analyzed diabetes development in mice whose spleen or pancreatic lymph nodes (panLNs) had been removed. Excision of panLNs (panLNx) at 3 wk protected mice against insulin autoantibodies (IAAs), insulitis, and diabetes development almost completely, but had no effect when performed at 10 wk. The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells. That panLNs are dispensable during adult life was confirmed by the capacity of 10-wk-old panLNx irradiated recipients to develop diabetes upon transfer of diabetogenic T cells. In contrast, splenectomy had no effect at any age. Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did. Thus, in normal NOD mice, autoreactive T cell initial priming occurs in LNs draining the target organ of the disease from 3 wk of age.

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CY injection failed to induce spontaneous diabetes in mice panLNx at 3 wk, whereas it accelerated diabetes in mice MLNx at 3 wk. CY was administered 5 and 7 wk after excision of panLN or MLN. Incidence of the disease was followed for 28 d.
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fig4: CY injection failed to induce spontaneous diabetes in mice panLNx at 3 wk, whereas it accelerated diabetes in mice MLNx at 3 wk. CY was administered 5 and 7 wk after excision of panLN or MLN. Incidence of the disease was followed for 28 d.

Mentions: CY, an immunosuppressive drug, accelerates diabetes in NOD mice in which insulitis is installed, that is from around 5 wk of age. The disease results from regulatory T cell elimination that allows autoreactive T cells to exert their function (12). After two injections, 2 wk apart, of CY administered 4–5 wk after surgery (when mice were aged 7–8 wk), diabetes developed in only 20% of panLNx mice, whereas 94% of sham-operated animals became diabetic during the following 3–4 wk (P < 0.0001) (Fig. 4 A). Interestingly, these results are similar to the incidence of spontaneous diabetes in the two groups of mice at 28 wk of age. Analysis of insulitis in 12-wk-old mice resistant to CY treatment showed that 50% of the islets in panLNx mice were free of infiltrate versus only 6% in control mice (Fig. 2 B). To verify the specific effect of panLNx, mice MLNx at 3 wk of age were treated with CY when 8 wk old. Diabetes developed in MLNx mice as efficiently as in control mice (P > 0.05; Fig. 4 B).


Pancreatic lymph nodes are required for priming of beta cell reactive T cells in NOD mice.

Gagnerault MC, Luan JJ, Lotton C, Lepault F - J. Exp. Med. (2002)

CY injection failed to induce spontaneous diabetes in mice panLNx at 3 wk, whereas it accelerated diabetes in mice MLNx at 3 wk. CY was administered 5 and 7 wk after excision of panLN or MLN. Incidence of the disease was followed for 28 d.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193939&req=5

fig4: CY injection failed to induce spontaneous diabetes in mice panLNx at 3 wk, whereas it accelerated diabetes in mice MLNx at 3 wk. CY was administered 5 and 7 wk after excision of panLN or MLN. Incidence of the disease was followed for 28 d.
Mentions: CY, an immunosuppressive drug, accelerates diabetes in NOD mice in which insulitis is installed, that is from around 5 wk of age. The disease results from regulatory T cell elimination that allows autoreactive T cells to exert their function (12). After two injections, 2 wk apart, of CY administered 4–5 wk after surgery (when mice were aged 7–8 wk), diabetes developed in only 20% of panLNx mice, whereas 94% of sham-operated animals became diabetic during the following 3–4 wk (P < 0.0001) (Fig. 4 A). Interestingly, these results are similar to the incidence of spontaneous diabetes in the two groups of mice at 28 wk of age. Analysis of insulitis in 12-wk-old mice resistant to CY treatment showed that 50% of the islets in panLNx mice were free of infiltrate versus only 6% in control mice (Fig. 2 B). To verify the specific effect of panLNx, mice MLNx at 3 wk of age were treated with CY when 8 wk old. Diabetes developed in MLNx mice as efficiently as in control mice (P > 0.05; Fig. 4 B).

Bottom Line: The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells.In contrast, splenectomy had no effect at any age.Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did.

View Article: PubMed Central - PubMed

Affiliation: Centre National de la Recherche Scientifique Unité Mixte de Recherche 8603, Université René Descartes, Hôpital Necker, 75015 Paris, France.

ABSTRACT
Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that results from the destruction of insulin secreting beta cells by diabetogenic T cells. The time and location of the encounter of autoantigen(s) by naive autoreactive T cells in normal NOD mice are still elusive. To address these issues, we analyzed diabetes development in mice whose spleen or pancreatic lymph nodes (panLNs) had been removed. Excision of panLNs (panLNx) at 3 wk protected mice against insulin autoantibodies (IAAs), insulitis, and diabetes development almost completely, but had no effect when performed at 10 wk. The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells. That panLNs are dispensable during adult life was confirmed by the capacity of 10-wk-old panLNx irradiated recipients to develop diabetes upon transfer of diabetogenic T cells. In contrast, splenectomy had no effect at any age. Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did. Thus, in normal NOD mice, autoreactive T cell initial priming occurs in LNs draining the target organ of the disease from 3 wk of age.

Show MeSH
Related in: MedlinePlus