Authors [Ref] Animal model Intervention Th1/Th17 Details   Vukkadapu et al.,  [39]   BDC2.5/ NOD mice   -   ↑ IL-17   Upregulation of Il17 gene in pancreas and increased IL-17 plasma levels during disease onset. Miljkovic et al.,  [40] STZ induced diabetes - ↑ IL-17 Increased IL-17 level in diabetic animals, IL-17 promoted upregulation of iNOS and increased beta cell toxicity. Mensah-Brown et al., [42] STZ induced diabetes IL-23 administration ↑ IFN-γ ↑ IL-17 Enhanced diabetogenic process, increased pancreatic inflammation and beta cell loss. Jain et al., [43] NOD mice Ig-GAD2 ↑ IFN-γ ↓ IL-17 Delayed T1D onset at insulitis stage, increased production of IFN-γ and inhibition of IL-17 secretion: reduced islet inflammation, restored normoglycemia at prediabetic stage. Emamaullee et al., 2009 [44] NOD mice Anti-IL-17 antibody or Recombinant IL-25 ↓ IL-17 Inhibition of Th17 cells on effector phase: Prevented progression of T1D, reduced islet inflammation and autoantibody formation. IL-25 treatment: restored euglycemia, reduced frequency of Th2 and Th17 cells, increased Treg population. Liu et al., [45] NOD mice and NOD.Idd3 mice - ↑ IL-17 Cells from NOD mice: increased production of IL-21, increased Th17 differentiation, increased production of pro-Th17 mediators by APCs. Zhang et al., [46] NOD mice IL-12 administration ↑ IFN-γ ↓ IL-17 Prevention of T1D development, decreased insulitis, increased healthy islets, decreased Th-17 cytokines levels. Spolski et al., [47] IL-21 knockout NOD mice - ↓ IL-17 Resistance of T1D development, reduced numbers of Th17 cells and IL-17 levels. Zhao et al., [49] NOD mice Bone marrow stromal cells ↓ IL-17 = IFN-γ Decreased blood glucose levels, decreased insulitis, increased Treg cells and decreased Th17 cells. Wang et al., [50] STZ induced diabetes T-cell vaccination ↓ IFN-γ ↓ IL-17 Decreased blood glucose levels, decreased Th1 and Th17 cytokines, increased Th2 cytokines. Transference of Th17 cells accelerated disease development. Yaochite et al., [51] STZ induced diabetes (IL-17 receptor deficient mice) - ↓ IL-17 Absence of IL-17 signaling: impaired diabetes development, reduced peri-insulits, increased beta cell mass preservation. Shi et al., [53] NOD mice - ↑ IL-17 NOD x Balb/c mice: Decreased Treg cells, increased Th17 cells. Diabetic NOD x Nondiabetic NOD: higher Th17/Treg ratio. Bending et al., [56] Adoptive transfer system (Th17 cells from BDC2.5 mice to NOD/SCID mice) - Th17 →Th1 Tranfer of Th17 cells induced diabetes in NOD/SCID recipient after conversion into Th1 cells. Neutralizing IFN-γ antibody prevented disease development, anti-IL-17 antibody had no effect. Martin-Orozco et al., [57] Adoptive transfer system (Th17 cellsin vitro-differentiated from BDC2.5 mice to NOD/SCID mice) - Th17 →Th1 Transfer of Th17 cells induced diabetes in NOD/SCID recipient after conversion into Th1 cells.   Wan et al., [54]   Adoptive transfer system (Th17 cells in vitro-differentiated from BDC2.5 mice to NOD/SCID and NOD mice)   -   Th17→Th1 (NOD/SCID mice) Stable Th17 (NOD mice)   NOD/SCID recipient: Transferred Th17 cells converted into Th1 cells to promote disease. NOD recipient: Absence of conversion, promoted pancreatic inflammation without clinical diabetes.     Van et al., [71]   Adoptive transfer system (splenocytes from NOD mice to NOD/SCID mice)   All-trans retinoic acid   ↓ IFN-γ = IL-17   Inhibition of T1D development, decreased islet inflammation, suppression of Th1 but not Th17 cells, Treg expansion. Joseph et al., [72] IL-17 knockdown NOD mice - Absence of  IL-17 No effect on frequency or disease onset. Dispensable role of IL-17 in T1D pathogenesis. Van Belle et al., [55] RIP-LCMV mice - Absence of IL-17 T1D development in absence of detectable IL-17A production. Dispensable role of IL-17A in T1D pathogenesis. Ankathatti Munegowda et al., [52] Adoptive transfer system (OVA-specific Th17 cells to RIP-OVA mice) - - Transferred Th17 cells stimulated CD8+ T cells. Activated CD8+ T cells promoted islets destruction via perforin-pathway. Indirect role of Th17 cells in T1D pathogenesis. Lau et al., [73] Bio-breeding diabetes prone rats (BBDP rats) Lactobacilus johnsonii (LjN6.2) ↑ IL-17 LjN6.2 feeding: Diabetes resistance, increased IL-17, IL-23 and IL-6 levels. Protective role of Th17 immune response. Nikoopour et al., [77] NOD mice Mycobacterial adjuvants ↑ IL-17 Prevention of T1D onset, increased levels of IL-17 in spleen, lymph nodes and pancreas. Transference of polarized Th17 cells from CFA-treated NOD mice into NOD/SCID recipient delayed disease onset: important role of IL-17 in this protection. Tse et al., [78] NAPDH oxidase deficient NOD mice - ↓IFN-γ ↑ IL-17 NADPH oxidase deficiency promoted Th17 polarization: protection against T1D and decreased insulitis. Abbreviations: T1D: Type 1 Diabetes; NOD mice: Non-Obese Diabetic Mice; STZ: Streptozotocin; SCID: Severe Combined Immunodeficiency; Treg cells: Regulatory T cells; RIP-LCMV: Rat Insulin Promoter-Lymphocytic Choriomeningitis Virus; OVA: Ovalbumin; CFA: Complete Freund´s Adjuvant.

Table 2: Investigations about the role of Th17 immune response in animal models of T1D.