Adjuvant Immunotherapy Increases β Cell Regenerative Factor Reg2 in the Pancreas of Diabetic Mice

Abstract

Insulin-producing β cells can partially regenerate in adult pancreatic tissues, both in human and animal models of type 1 diabetes (T1D). Previous studies have shown that treatment with mycobacterial adjuvants such as CFA and bacillus Calmette-Guérin prevents induction and recurrence of T1D in NOD mice with partial recovery of β cell mass. In this study, we investigated factors involved in the regeneration of β cells in the pancreas of NOD mice during diabetes development and after treatment with adjuvants. The Regeneration (Reg) gene family is known to be involved in regeneration of various tissues including β cells. Reg2 expression was found to be upregulated in pancreatic islets both during diabetes development and as a result of adjuvant treatment in diabetic NOD mice and in C57BL/6 mice made diabetic by streptozotocin treatment. The upregulation of Reg2 by adjuvant treatment was independent of signaling through MyD88 and IL-6 because it was not altered in MyD88 or IL-6 knockout mice. We also observed upregulation of Reg2 in the pancreas of diabetic mice undergoing β cell regenerative therapy with exendin-4 or with islet neogenesis-associated protein. Reg2 expression following adjuvant treatment correlated with a reduction in insulitis, an increase in insulin secretion, and an increase in the number of small islets in the pancreas of diabetic NOD mice and with improved glucose tolerance tests in streptozotocin-treated diabetic C57BL/6 mice. In conclusion, adjuvant immunotherapy regulates T1D in diabetic mice and induces Reg2-mediated regeneration of β cells.

Transcriptional activation of Reg2 and Reg3β genes by glucocorticoids and interleukin-6 in pancreatic acinar and islet cells

“…mice; the increase correlated with a reduction in insulitis (Huszarik et al, 2010). On the other hand, our result of C57B/L6 mice did not support previously reported Reg2 expression in pancreatic b-cells of NOD mice, which might be caused by strain differences (Gurr et al, 2007).…”

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

“…Reg2 showed a different pattern from Reg1; it tended to increase due to damage but was significantly upregulated by the combination of damage plus IMT504, indicating that it could be one of the mechanisms by which IMT504 induces ␤-cell regeneration, as evidenced by increased ␤-cell proliferation in the short-term analysis and recuperation of ␤-cell area in the long-term analysis. Similar to our results, other authors have demonstrated that Reg2 plays a dominant role in endogenous ␤-cell regeneration following adjuvant immunotherapy in diabetic mice (24,25). Interestingly, all murine Reg genes carry one or more IL-6 response elements in their 5= flanking region (20).…”

Restrain of beta-cell destruction and stimulation of beta-cell regeneration in type 1 diabetes

“…[35] podkreślają raczej możliwość samoreplikacji istnieją-cych komórek beta niż ich powstawanie z komó-rek macierzystych. Poza tym różne czynniki mogą wpływać na regenerację komórek beta poprzez wzrost ekspresji Reg l i Reg 2 (regenerating genes) w wyspach [36,37]. Levetan i wsp.…”

“…2015.14.3.52. [35][36][37][38][39][40] Próby hamowania destrukcji oraz stymulacji odnowy komórek beta trzustki w cukrzycy typu l beta może być efektem proliferacji prekursorów (preexisting) komórek beta. Collombat i wsp.…”