Adjuvant immunotherapy increases beta cell regenerative factor Reg2 in the pancreas of diabetic mice.
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.
Huszarik
Katrina
K
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
Wright
Benjamin
B
Keller
Christina
C
Nikoopour
Enayat
E
Krougly
Olga
O
Lee-Chan
Edwin
E
Qin
Hui-Yu
HY
Cameron
Mark J
MJ
Gurr
Werner K
WK
Hill
David J
DJ
Sherwin
Robert S
RS
Kelvin
David J
DJ
Singh
Bhagirath
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D017024:Chemotherapy, Adjuvant; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology; D015870:Gene Expression; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C000612141:REG3A protein, human; C490253:Reg3b protein, mouse; D005620:Freund's Adjuvant