Remission of autoimmune diabetes by anti-TCR combination therapies with anti-IL-17A or/and anti-IL-6 in the IDDM rat model of type 1 diabetes

Abstract

Background: The cytokine IL-17 is a key player in autoimmune processes, while the cytokine IL-6 is responsible for the chronification of inflammation. However, their roles in type 1 diabetes development are still unknown. Methods: Therefore, therapies for 5 days with anti-IL-17A or anti-IL-6 in combination with a T cell-specific antibody, anti-TCR, or in a triple combination were initiated immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm (IDDM) rat, a model of human type 1 diabetes. Results: Monotherapies with anti-IL-6 or anti-IL-17 showed no sustained anti-diabetic effects. Only the combination therapy of anti-TCR with anti-IL-6 or anti-IL-17 at starting blood glucose concentrations up to 12 mmol/l restored normoglycaemia. The triple antibody combination therapy was effective even up to very high initial blood glucose concentrations (17 mmol/l). The β cell mass was raised to values of around 6 mg corresponding to those of normoglycaemic controls. In parallel, the apoptosis rate of β cells was reduced and the proliferation rate increased as well as the islet immune cell infiltrate was strongly reduced in double and abolished in triple combination therapies. Conclusions: The anti-TCR combination therapy with anti-IL-17 preferentially raised the β cell mass as a result of β cell proliferation while anti-IL-6 strongly reduced β cell apoptosis and the islet immune cell infiltrate with a modest increase of the β cell mass only. The triple combination therapy achieved both goals in a complimentary antiautoimmune and anti-inflammatory action resulting in sustained normoglycaemia with normalized serum C-peptide concentrations.

Evaluation of Some Inflammatory Cytokines Levels as A Marker for Diabetes

“…In addition, the outcomes are in line with Robinson, et al [19] who mentioned that IL-6 is a pleiotropic cytokine that can be found in high levels in the blood and vitreous of DR (diabetic retinopathy) patients. Jorns, et al [20] who reported that during the inflammation process in the T1D pancreas, the pro-inflammatory cytokine IL-6 was expressed in all immune cell subtypes. Tsalamandris, et al [21] indicated that IL-6 plays a role in pathogenesis of diabetic.…”

Advanced Glycation End-Products (AGEs) of Lysine and Effects of Anti-TCR/Anti-TNF-α Antibody-Based Therapy in the LEW.1AR1-iddm Rat, an Animal Model of Human Type 1 Diabetes

“…Additional RAGE ligands include the high-mobility group of box protein 1 (HMGB1), S100 proteins, β-amyloid, β-sheet fibrils and lipopolysaccharide [33]. Research findings gained over the last two decades argue for a link of AGEs and RAGE to the T1D pathogenesis, yet a possible role of AGEs in islet function and survival within homeostasis and disease states is still elusive [28].…”

“…Currently, RAGE and AGEs are the focus of therapy for diabetes' conditions such as diabetic retinopathy [20], as well as in other inflammatory diseases such as myasthenia gravis [21]. We have shown that the LEW.1AR1-iddm rat model of human T1D [22] is a useful experimental tool to study various aspects, including development, progression and therapy of T1D [23][24][25][26][27][28][29]. In a previous study [29], we investigated possible implications of dimethylation and citrullination of Arg residues in proteins in four organs of LEW.1AR1-iddm rats under different diabetic metabolic conditions compared to normoglycaemic healthy control rats.…”

Cross-Sectional Analysis of the Involvement of Interleukin-17A in Diabetic Retinopathy in Elderly Individuals with Type 2 Diabetes Mellitus

“…20 Our previous research shows that the higher the serum IL-17A level, the higher the incidence and severity of DR. The underlying mechanism can be summarized as: (1) IL-17A can trigger the destruction of the fundus vascular barrier as well as increase the degree of inflammation of 10 Global DR research studies have revealed that a longer T2DM duration, increasing age, higher HbA1c levels, and poorer blood pressure control were strongly correlated with DR. 13,22 In this study, the longer the DM duration, the higher the prevalence and severity of DR, which is consistent with previous studies. 23 Many previous studies have shown that FCP is related to DR. 24 An earlier study showed that after adjustment for confounding factors, C-peptide and insulin levels were significantly correlated with extent of DR in Latinos with type 2 diabetes.…”

“…Triple combination therapy effectively induced blood glucose homeostasis involving normalized serum C-peptide concentrations by controlling autoimmunity and improving anti-inflammatory effects. 10 IL-17A may be involved in the pathological process of DR, but the relationship between them is still unclear. As the relationship between IL-17A and DR is complicated, more research is needed.…”