T helper 17 cells and interleukin-17 immunity in type 1 diabetes: From pathophysiology to targeted immunotherapies

Table 1 Summary of the main studies on the use of Th17- and interleukin-17-targeted therapies in animal models of autoimmune diabetes and related chronic complications

Animals	Induced experimental diabetes and/or related chronic complication	Intervention	Results	Ref.
NOD/LtJ and NOD-RAG−/− mice (NOD.129S7-Rag1tm1Mom/J)	NOD mice as a model of spontaneous autoimmune diabetes	Inhibition of Th17 cells using both neutralizing anti-IL-17 antibodies and recombinant IL-25	Reduction in peri-islet T-cell infiltrates and GAD65 antibody production; increase in the frequency of regulatory T cells. IL-25 therapy was superior to anti-IL-17 treatment mature diabetes since it determined a period of remission from new-onset diabetes in 90% of the treated animals	Emamaullee et al[56], 2009
C57BL/6 mice	STZ-induced diabetes; signs of diabetic retinopathy	Anti-IL-17A intravitreal injection treatment. Mouse IL-17A antibody (a neutralizing, monoclonal IgG1 antibody binding to IL-17A, and inhibiting IL-17A activity) was injected intravitreally	Decrease in retinal inflammation and ZO-1 degradation within the retinal endothelium	Zhou et al[83], 2023
Male C57BL/6J inbred mice	Autoimmune diabetes induced by multiple low doses of STZ	TCV aimed to inhibit autoimmune diabetes in mice through the suppression of Th17 cells	TCV decreased hyperglycemia, preserved the number of healthy pancreatic islets and increased insulin production in the pancreatic islets; moreover, TCV led to reduced production of both IL-17 and IL-23 in intrapancreatic infiltrating lymphocytes via marked inhibition of mRNA level of RORγt and Stat3 phosphorylation	Wang et al[84], 2011
NOD/SCID mice	Mouse model of T1D	Authors investigated whether mouse Th17 cells with specificity for an islet antigen can induce diabetes upon transfer into NOD/SCID recipient mice. Authors also investigated whether use of neutralizing IL-17-specific antibodies can prevent autoimmune diabetes	Induction of diabetes in NOD/SCID mice through adoptive transfer of Th1 cells from BDC2.5 transgenic mice was prevented by treatment of the recipient mice with a neutralizing IFN-γ-specific antibody, suggesting a major role of Th1 cells in the induction of disease in this animal model of T1D. Transfer of highly purified Th17 cells from BDC2.5 transgenic mice caused diabetes in NOD/SCID recipients with similar rates of onset as it was observed after transfer of Th1 cells. However, treatment with neutralizing IL-17-specific antibodies did not prevent the disease. Instead, the transferred Th17 cells, which were completely devoid of IFN-γ at the time of transfer, rapidly converted to secrete IFN-γ in the NOD/SCID recipient mice. These results indicate the existence of a plasticity of Th17 cell commitment towards a Th1-like profile	Bending et al[80], 2009
Female NOD/LtJ mice	Mouse model of T1D	Administration of the selective RORα/γ inverse agonist SR1001	SR1001-treated mice showed a substantial reduction in the incidence of diabetes and insulitis. SR1001 raised the frequency of CD4+ Foxp3+ Tregs, decreased the production of islet autoantibodies, and reduced the expression of pro-inflammatory cytokines (particularly the expression of Th17-mediated cytokines)	Solt et al[78], 2015
Male 8-week-old C57BL/6 mice	Intraperitoneal injections of STZ to induce diabetic retinopathy	Diabetic retinopathy model mice were treated with anti-IL-17A or anti-IL-17RA monoclonal antibodies administered into the vitreous cavity	Intravitreal injections of anti-IL-17A or anti-IL-17RA monoclonal antibodies reduced Müller cell dysfunction, vascular leakage, vascular leukostasis, tight junction protein downregulation, as well as ganglion cell apoptosis within the retina	Qiu et al[85], 2017
Ins2Akita (Akita) mice	T1D model with a spontaneous mutation in the insulin 2 gene leading to beta-cell apoptosis. STZ was also used to induce a diabetic model in MIN6 cells, a mouse insulinoma cell line	Anti-IL-17RA-neutralizing antibody used in MIN6 cells	IL-17A-knockout Akita mice showed reduced blood glucose concentrations and raised serum insulin levels. IL-17A deficiency decreased the production of the pro-inflammatory cytokines TNF-α, IL-1β, and IFN-γ in Akita mice, whereas IL-17RA expression in MIN6 cells was upregulated by IL-17A. IL-17A enhanced the expression of TNF-α, IL-1β, IFN-γ and iNOS, while it further augmented the STZ-induced inflammatory responses in MIN6 cells. IL-17A exacerbated STZ-induced MIN6 cell apoptosis and impairment in insulin secretion. Blocking IL-17RA with the use of an anti-IL-17RA-neutralizing antibody reduced all the aforementioned deleterious effects exerted by IL-17A on MIN6 cells. Overall, IL-17A deficiency alleviated hypoinsulinemia, hyperglycemia and inflammatory response in Akita mice. IL-17A exerted deleterious effects (alone and in combination with STZ) on pancreatic beta cells through the IL-17RA pathway	Qiu et al[86], 2021
Male WT C57BL/6 mice	Intraperitoneal administration of STZ to induce diabetes and diabetic nephropathy	Use of IL-17 knockout mice or administration of neutralizing anti-IL-17 monoclonal antibody	IL-17-deficient mice were protected against the progression of diabetic nephropathy, showing reductions in glomerular damage, albuminuria, macrophage accumulation, and renal fibrosis at 12 and 24 wk. Administration of the anti-IL-17 monoclonal antibody to diabetic wild-type mice exerted similar protective effects. IL-17 deficiency also mitigated the up-regulation of pro-inflammatory and pro-fibrotic genes such as TNF-α, IL-6, CCL2, TGF-β and CXCL10 in diabetic kidneys. In vitro co-stimulation with recombinant IL-17 and high glucose exerted synergistic effects in increasing the expression of pro-inflammatory genes in cultured renal tubular cells and podocytes	Ma et al[87], 2019

NOD mice: Non-obese diabetic mice; T1D: Type 1 diabetes; IL: Interleukin; Th-17: T helper 17; FOXP3: Forkhead box P3; RORγt: Retinoic acid-related orphan receptor gamma t; Tregs: Regulatory T cells; STZ: Streptozotocin; TCV: T-cell vaccination; Stat3: Signal transducer and activator of transcription 3; ZO-1: Zonula Occludens-1; IFN: Interferon; TNF: Tumor necrosis factor; TGF: Transforming growth factor; iNOS: Inducible nitric oxide synthase; SCID: Severe combined immunodeficiency; WT: Wild-type.

Table 2 Summary of the main ongoing clinical studies of Th17- and interleukin-17-targeted therapies in patients with new-onset type 1 diabetes

Study name	Study status and planned number of participants	Country	Study type	Study outcomes	ClinicalTrials.gov ID
Clinical Phase II/III Trial of Ustekinumab to Treat Type 1 Diabetes (UST1D2)	Recruiting; 66 adults	Canada	Randomized, placebo-controlled, double-blinded, multicenter phase II/II study conducted on 66 adult subjects (18-35 yr old) with recent-onset T1D. Ustekinumab is a fully human monoclonal antibody binding to the shared p40 subunit of IL-12 and IL-23, thus targeting the development of Th1 cells and Th17 cells. Planned study duration: Patients will be followed for 78 wk after the administration of the first ustekinumab dose. There will be a total of 10 study visits over the 78-wk period, three of which will be non-dosing and follow-up visits	Assessment of the efficacy of ustekinumab in counteracting the decline in mixed meal-stimulated C-peptide values in adult patients with recent-onset T1D	NCT03941132
Ixekizumab Diabetes Intervention Trial (I-DIT)	Recruiting; 127 patients	Sweden	Double-blind, placebo-controlled prospective phase 2 trial conducted on adult patients with newly diagnosed T1D. Planned study duration: 52 wk	Assessment of the efficacy of ixekizumab (an anti-IL-17A humanized monoclonal antibody) in counteracting the decline in mixed meal-stimulated C-peptide values in adult patients with newly diagnosed T1D	NCT04589325

T1D: Type 1 diabetes; IL: Interleukin; Th: T helper.