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T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice.

Pakala SV, Kurrer MO, Katz JD - J. Exp. Med. (1997)

Bottom Line: Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4.These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease.Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

ABSTRACT
Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

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Anti–IL-10 mAb treatment protects NOD.scid mice from  Th2-mediated disease. Mice were treated with 250 μg of purified mAb  against IL-10 (2A5) and IL-4 (11B11) every 72 h. Open circles represent  anti–IL-10–treated mice and closed circles represent anti–IL-4–treated  mice. Diabetes was assessed by measuring blood glucose. Mice with two  consecutive blood sugar readings above 250 mg/dl were considered diabetic. Onset was dated to the first of the two consecutive readings.
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Figure 4: Anti–IL-10 mAb treatment protects NOD.scid mice from Th2-mediated disease. Mice were treated with 250 μg of purified mAb against IL-10 (2A5) and IL-4 (11B11) every 72 h. Open circles represent anti–IL-10–treated mice and closed circles represent anti–IL-4–treated mice. Diabetes was assessed by measuring blood glucose. Mice with two consecutive blood sugar readings above 250 mg/dl were considered diabetic. Onset was dated to the first of the two consecutive readings.

Mentions: To rule out the contribution of neutrophils and granulocytes in the pancreatitis associated with Th2 T cell transfer, we treated mice with a granulocyte-specific mAb RB6 at concentrations sufficient to severely deplete granulocytes in vivo (24, 25). We found no change in disease or in the characteristics of the Th2 lesion when granulocytes and neutrophils were depleted from mice injected with Th2 cells (data not shown). However, when we treated Th2 recipient NOD.scid mice with neutralizing antibodies against IL-10, a Th2 cytokine previously shown to have a major effect on autoimmune diabetes, the Th2-mediated disease was significantly ameliorated. This was not true for another Th2 cytokine, IL-4 (Fig. 4). NOD.scid mice received either 250 μg of anti–IL-4, anti– IL-10, or saline every 72 h, with the first dose 24 h before infusion of the Th2 T cells. As depicted in Fig. 4, anti–IL-4 treatment did not protect from diabetes, whereas anti–IL-10 significantly delayed or abrogated the Th2 pathology. Histology performed on pancreas from these mice indicate no change in the lesion characteristics, yet anti–IL-10 treatment substantially protected against Th2 lesions, suggesting that IL-10 contributes to the pathology of Th2 disease.


T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice.

Pakala SV, Kurrer MO, Katz JD - J. Exp. Med. (1997)

Anti–IL-10 mAb treatment protects NOD.scid mice from  Th2-mediated disease. Mice were treated with 250 μg of purified mAb  against IL-10 (2A5) and IL-4 (11B11) every 72 h. Open circles represent  anti–IL-10–treated mice and closed circles represent anti–IL-4–treated  mice. Diabetes was assessed by measuring blood glucose. Mice with two  consecutive blood sugar readings above 250 mg/dl were considered diabetic. Onset was dated to the first of the two consecutive readings.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198973&req=5

Figure 4: Anti–IL-10 mAb treatment protects NOD.scid mice from Th2-mediated disease. Mice were treated with 250 μg of purified mAb against IL-10 (2A5) and IL-4 (11B11) every 72 h. Open circles represent anti–IL-10–treated mice and closed circles represent anti–IL-4–treated mice. Diabetes was assessed by measuring blood glucose. Mice with two consecutive blood sugar readings above 250 mg/dl were considered diabetic. Onset was dated to the first of the two consecutive readings.
Mentions: To rule out the contribution of neutrophils and granulocytes in the pancreatitis associated with Th2 T cell transfer, we treated mice with a granulocyte-specific mAb RB6 at concentrations sufficient to severely deplete granulocytes in vivo (24, 25). We found no change in disease or in the characteristics of the Th2 lesion when granulocytes and neutrophils were depleted from mice injected with Th2 cells (data not shown). However, when we treated Th2 recipient NOD.scid mice with neutralizing antibodies against IL-10, a Th2 cytokine previously shown to have a major effect on autoimmune diabetes, the Th2-mediated disease was significantly ameliorated. This was not true for another Th2 cytokine, IL-4 (Fig. 4). NOD.scid mice received either 250 μg of anti–IL-4, anti– IL-10, or saline every 72 h, with the first dose 24 h before infusion of the Th2 T cells. As depicted in Fig. 4, anti–IL-4 treatment did not protect from diabetes, whereas anti–IL-10 significantly delayed or abrogated the Th2 pathology. Histology performed on pancreas from these mice indicate no change in the lesion characteristics, yet anti–IL-10 treatment substantially protected against Th2 lesions, suggesting that IL-10 contributes to the pathology of Th2 disease.

Bottom Line: Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4.These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease.Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

ABSTRACT
Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

Show MeSH
Related in: MedlinePlus