Table 1.
Cytokines in T1D
| Cytokines | Pros | Cons | Outcomes of targeting cytokines in animals | Outcomes of targeting cytokines in humans |
|---|---|---|---|---|
| IL‐2 | Activating Tregs; shifting Th1 cytokine‐producing cells to Th2 and Th3 cytokine‐producing cells | Expanding effector T cells and NK cells; inducing IL‐17 | Low‐dose IL‐2 prevented disease development; IL‐2 combined with sirolimus induced disease remission | IL‐2 was well tolerated and increased the number of Tregs in patients with T1D |
| IL‐4 | Restoring IL‐12; activating and expanding iNKT and Tregs; activating PI3K and JAK/STAT pathways via IL‐4R in β cells | None | IL‐4 overexpression lowered the diabetes incidence, whereas complete elimination of IL‐4 did not accelerate or intensify insulitis | None |
| IL‐13 | Shifting a type 1 to a type 2 cytokine profile; increasing IgE production; promoting STAT6 and antiapoptotic gene expression in β cells | None | IL‐13 suppressed β‐cell destruction and prevented T1D development | None |
| IL‐10 | Inducing tolerogenic DCs, Tregs and Bregs; increasing Th2‐type cytokines and suppressing Th1‐type cytokines | Facilitating the apoptosis of CD4−CD8− T cells | IL‐10 prevented disease development, whereas local production of IL‐10 accelerated diabetes onset | None |
| TGF‐β | Proliferating Tregs; polarising islet antigen‐specific T‐cell responses towards a Th2 response | Promoting fibrosis and affecting pancreatic structure | TGF‐β inhibited the development of diabetes | None |
| IL‐1 | None | Triggering β‐cell apoptosis; inducing local inflammation | IL‐1R deficiency did not prevent disease progression | Anti‐IL‐1 antibodies (anakinra and canakinumab) did not prevent the decline in β‐cell function |
| IL‐6 | None | Promoting the migration and inflammatory responses of effector T cells | None | Therapeutic blockade of IL‐6 is being explored in clinical trials (NCT02293837) |
| TNF‐α | None | Inducing DC maturation; activating islet antigen‐specific T cells; accelerating β‐cell apoptosis | The protective effects of TNF‐α blockade on T1D were age‐dependent | Neutralisation of TNF‐α preserved β‐cell function in patients with recent‐onset T1D |
| IFN‐α | None | Augmenting Th1 responses; promoting the expression of HLA‐I molecules in β cells; mediating β‐cell endoplasmic reticulum stress and apoptosis | Blockade of IFN‐α signalling prevented disease development, whereas a certain dose of IFN‐α inhibited and prevented diabetes | Low‐dose IFN‐α had a beneficial effect in young patients with recent‐onset T1D |
| IFN‐γ | Inducing inhibitory STAT1 expression; suppressing diabetogenic CD8+ T cells and Th1‐type cytokines | Inducing aberrant expression of MHC‐I and MHC‐II in β cells | IFN‐γ had a dual role in T1D | None |
| IL‐15 | Enhancing Foxp3 expression in CD4+ Tregs; promoting Ly‐49+CD8+ Treg development | Proliferating and activating NK cells and CD8+ T cells | IL‐15 had a dual role in T1D | None |
| IL‐33 | Inducing Tregs; upregulating the expression of the ST2 molecule | None | IL‐33 prevented T1D development | None |
| IL‐35 | Inducing Tregs | None | IL‐35 prevented T1D development | None |
| IL‐12 | Suppressing proinflammatory cytokines; indirectly inhibiting Th17 cells | Increasing islet‐infiltrating CD4+ T cells | IL‐12 had a dual role in T1D | None |
| IL‐7 | Maintaining Tregs that selectively express IL‐7Rα | Promoting the differentiation of IFN‐γ‐producing cells; decreasing PD‐1 expression in diabetogenic T cells | Blockade of IL‐7 signalling reversed diseases | None |
| IL‐17 | None | Activating Th17 cells | Blockade of IL‐17 signalling prevented T1D development | None |
| IL‐21 | None | Promoting Th17 differentiation, DCs and Tfh migration | Blockade of IL‐21 signalling prevented T1D development. | Therapeutic blockade of IL‐21 is being explored in clinical trials (NCT02443155) |
| IL‐22 | Upregulating the expression of Bcl‐2, Bcl‐xl, Reg1 and Reg2 in β cells | None | Neither IL‐22 nor an anti‐IL‐22 antibody affected residual β‐cell function in a diabetic mouse model | None |
| IL‐25 | Inhibiting Th17 cells; inducing Th2 cytokine secretion | None | IL‐25 delayed diabetes progression | None |