title: ST2 gene-deletion reveals a role of Foxp3+ regulatory T cells in diabetes modulation in BALB/c mice.
abstract: BALB/c mice are resistant to diabetes induced by multiple low doses of streptozotocin (MLD-STZ; 5 × 40 mg/kg body weight [b.w.]) regimen in contrast to C57/BL6 mice. The deletion of ST2 gene renders BALB/c mice susceptible to diabetes induction. Cyclophosphamide (CY) in the dose of 175 mg/kg b.w. eliminated CD4+Foxp3+ regulatory T cells (Tregs) and enhanced disease severity in C57/BL6 mice, but it did not overcome resistance to diabetes in BALB/c mice and did not affect diabetes progression in ST2 knock-out (ST2KO) mice. We argued that a lower dose of CY may selectively eliminate Tregs while sparing effector T cells in BALB/c mice. Indeed, only a very low dose of CY (50 mg/kg b.w.) enhanced diabetes severity in ST2KO mice. This treatment eliminated Tregs in pancreatic lymph nodes in ST2KO mice, while markedly increasing the influx of CD8+, CD4+TNF-α+, and CD4+IFN-γ+ effector T cells (Teffs) in pancreata. Also, the aggravation of diabetes was accompanied with increased serum levels of TNF-α, IFN-γ, and IL-17. Taken together, our data suggest that the prevailing Th2 immune response in BALB/c mice may be responsible for the resistance to MLD-STZ diabetes and that ST2 gene deletion reveals the role of highly cyclophosphamide sensitive CD4+Foxp3+ regulatory T cells in the pancreatic lymph nodes in diabetes modulation.
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medicine, University of Kragujevac, Kragujevac, Serbia. zdravkovic_nemanja@yahoo.com
authors.forename: Nemanja
authors.initials: N
authors.lastname: Zdravkovic
authors.forename: Sladjana
authors.initials: S
authors.lastname: Pavlovic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Zdravkovic
authors.forename: Nada
authors.initials: N
authors.lastname: Pejnovic
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Arsenijevic
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C486189:Il1rl1 protein, mouse; D007166:Immunosuppressive Agents; D000072179:Interleukin-1 Receptor-Like 1 Protein; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D018123:Receptors, Interleukin; D003520:Cyclophosphamide