Tellurium Compounds Prevent and Reverse Type-1 Diabetes in NOD Mice by Modulating α4β7 Integrin Activity, IL-1β, and T Regulatory Cells

Abstract

The study shows that treatment of NOD mice with either of two tellurium-based small molecules, AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate] or SAS [octa-O-bis-(R,R)-tartarate ditellurane] could preserve β cells function and mass. These beneficial effects were reflected in decreased incidence of diabetes, improved glucose clearance, preservation of body weight, and increased survival. The normal glucose levels were associated with increased insulin levels, preservation of β cell mass and increased islet size. Importantly, this protective activity could be demonstrated when the compounds were administered either at the early pre-diabetic phase with no or initial insulitis, at the pre-diabetic stage with advanced insulitis, or even at the advanced, overtly diabetic stage. We further demonstrate that both tellurium compounds prevent migration of autoimmune lymphocytes to the pancreas, via inhibition of the α4β7 integrin activity. Indeed, the decreased migration resulted in diminished pancreatic islets damage both with respect to their size, β cell function, and caspase-3 activity, the hallmark of apoptosis. Most importantly, AS101 and SAS significantly elevated the number of T regulatory cells in the pancreas, thus potentially controlling the autoimmune process. We show that the compounds inhibit pancreatic caspase-1 activity followed by decreased levels of the inflammatory cytokines IL-1β and IL-17 in the pancreas. These properties enable the compounds to increase the proportion of Tregs in the pancreatic lymph nodes. AS101 and SAS have been previously shown to regulate specific integrins through a unique redox mechanism. Our current results suggest that amelioration of disease in NOD mice by this unique mechanism is due to decreased infiltration of pancreatic islets combined with increased immune regulation, leading to decreased inflammation within the islets. As these tellurium compounds show remarkable lack of toxicity in clinical trials (AS101) and pre-clinical studies (SAS), they may be suitable for the treatment of type-1 diabetes.

The tellurium-based immunomodulator, AS101 ameliorates adjuvant-induced arthritis in rats

“…The ability of AS101 to react with vicinal thiols results in the functional inhibition of inflammatory integrins such as α4β1 (VLA‐4) and α4β7, and the prevention of inflammatory/autoreactive lymphocytes (α4β1 and α4β7‐expressing T cells and macrophages) extravasation into the relevant sites of inflammation. Similarly, treatment with AS101 was previously shown to reduce proinflammatory cytokines such as tumor necrosis factor (TNF)‐α, IL‐1β, interferon (IFN)‐γ, IL‐17, IL‐6 and IL‐18, with a concomitant increase of regulatory cells [16,17,20,21,24,28,29].…”

“…The redox modulating activities of AS101 ultimately results in a variety of beneficial biological effects [19]. Through its anti-inflammatory properties, AS101 confers protection, reverses damage and prevents progression of diseases in several autoimmune animal models [20][21][22][23][24] and septic mice [25].…”

“…The ability of AS101 to prevent diapedesis of inflammatory/autoreactive lymphocytes into inflamed tissues in various experimental inflammatory/autoimmune diseases [17,21,22,24] provided the rationale to explore this potential effect in the AIA animal model. Histopathological examination revealed severe joint destruction and active chronic inflammation accompanied by infiltration of mononuclear cells (lymphocytes and macrophages) into the cartilage and synovium in PBS-treated rats, with occasional areas of polymorphonuclear cells.…”

“…The VLA-4 (α4β1) integrin has been previously shown to play a significant role in the diapedesis of inflammatory leukocytes to sites of inflammation in both RA animal models and RA patients [9][10][11][12]. The main biological activity of AS101 has been attributed to the modulation of the functional activities of leukocyte integrins such as VLA-4 [16,17,20,24]. In our study, immunohistochemical staining revealed a massive infiltration of VLA4 + cells into the synovium of PBS-treated rats, paralleled with a reduction of inflammatory immune cells in blood vessels (Fig.…”

The inorganic chemicals that surround us: role of tellurium, selenium and zinc on behavioural functions in mammals

“…In addition, this organotellurium complex has shown some additional properties regarding immunological responses such as inhibition of the production of inflammatory cytokines, and ameliorating the pathogenic reactions of the experimental autoimmune encephalomyelitis [29]. Furthermore, AS101 restores and protects the dopaminergic neuronal activity in an animal model of Parkinson's disease [30], and reverse the deleterious effects of type 1 diabetes in NOD/ShiLt female mice [31], suggesting that Te could be participating in some key physiological processes in the organism.…”