title: Upregulating CD4+CD25+FOXP3+ regulatory T cells in pancreatic lymph nodes in diabetic NOD mice by adjuvant immunotherapy.
abstract: BACKGROUND
  Immunotherapy with Complete Freund's adjuvant (CFA) is effective in ameliorating autoimmunity in diabetic nonobese diabetic (NOD) mice. We investigated whether CFA treatment up-regulates CD4+CD25+Foxp3+ regulatory T cells and increases transforming growth factor (TGF)-beta1 production in diabetic NOD mice.
  
  
  METHODS
  New-onset diabetic NOD mice were treated with CFA and exendin-4, a potent analog of glucagon-like peptide-1. Reversal of diabetes was determined by monitoring blood glucose level. Ameliorating autoimmunity through immunoregulation was assessed by adoptive transfer. Regulatory T cells in the peripheral blood, spleen, thymus, and pancreatic nodes were measured. TGF-beta1 in plasma and the insulin content in the pancreas were also measured. Immunostainings for insulin and BrdU were performed.
  
  
  RESULTS
  New-onset diabetes could be reversed in 38% of NOD mice treated with CFA alone and in 86% of NOD mice treated with both CFA and exendin-4. Diabetes adoptive transfer by splenocytes from CFA-treated NOD mice was delayed. The percentage of CD4+CD25+Foxp3+ regulatory T cells in the pancreatic lymph nodes of CFA-treated NOD mice was significantly increased at 1, 5, and 15 to 17 weeks after treatment. TGF-beta1 in the plasma of CFA-treated NOD mice was also significantly increased. Combining CFA with exendin-4 treatment significantly increased the insulin content and the numbers of insulin and BrdU double-labeled beta cells in the islets.
  
  
  CONCLUSIONS
  Our results demonstrated that CFA treatment ameliorates autoimmunity in diabetic NOD mice by up-regulating CD4=CD25+Foxp3+ regulatory T cells and increasing TGF-beta1 production. Exendin-4 enhanced the effect of CFA on reversing diabetes in NOD mice by stimulating beta-cell replication.
authors.affiliation: Department of Surgery and Diabetes Institute for Immunology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Bole
authors.initials: B
authors.lastname: Tian
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hao
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.forename: Huimin
authors.initials: H
authors.lastname: Yi
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Brien
authors.forename: David E R
authors.initials: DE
authors.lastname: Sutherland
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Hering
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D049109:Cell Proliferation / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D000077270:Exenatide; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005620:Freund's Adjuvant / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010179:Pancreas / Q000187:drug effects* / Q000276:immunology; D010455:Peptides / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000097:blood; D015854:Up-Regulation; D014688:Venoms / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D001786:Blood Glucose; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007004:Hypoglycemic Agents; C508018:Il2ra protein, mouse; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit; D010455:Peptides; D053773:Transforming Growth Factor beta1; D014688:Venoms; D005620:Freund's Adjuvant; D000077270:Exenatide