Emerging Therapeutic Strategies to Restore Regulatory T Cell Control of Islet Autoimmunity in Type 1 Diabetes

Abstract

Despite many decades of investigation uncovering the autoimmune mechanisms underlying Type 1 Diabetes (T1D), translating these findings into effective therapeutics has proven extremely challenging. T1D is caused by autoreactive T cells that become inappropriately activated and kill the β cells in the pancreas, resulting in insulin insufficiency and hyperglycemia. A large body of evidence supports the idea that the unchecked activation and expansion of autoreactive T cells in T1D is due to defects in immunosuppressive regulatory T cells (Tregs) that are critical for maintaining peripheral tolerance to islet autoantigens. Hence, repairing these Treg deficiencies is a much sought-after strategy to treat the disease. To accomplish this goal in the most precise, effective and safest way possible, restored Treg functions will need to be targeted towards suppressing the autoantigen-specific immune responses only and/or be localized in the pancreas. Here we review the most recent developments in designing Treg therapies that go beyond broad activation or expansion of non-specific polyclonal Treg populations. We focus on two cutting-edge strategies namely ex vivo generation of optimized Tregs for re-introduction in T1D patients vs direct in situ stimulation and restoration of endogenous Treg function.

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

“…DKD, also known as diabetic nephropathy [ 9 , 10 , 11 , 12 , 13 ], is a common complication of diabetic mellitus, including both type 1 and type 2 diabetes. While type 1 diabetes is caused by lack of insulin due to pancreatic β cell destruction [ 14 , 15 , 16 ], type 2 diabetes could be caused by insulin resistance or insulin deficiency [ 17 , 18 , 19 , 20 , 21 , 22 ]. The hallmark of diabetes is a persistent high blood glucose content (hyperglycemia) that can damage a variety of tissues and cells [ 15 , 21 , 22 , 23 ].…”

Marker genes of incident type 1 diabetes in peripheral blood mononuclear cells of children: A machine learning strategy for large-p, small-n scenarios

“…There is emerging evidence on the role of EGR2 in the natural history of diabetes, through the development of insulin resistance which is increasingly observed in people with T1D [37] to the progression of complications [38, 39]. Recent studies which revealed crucial roles of EGR2 in the induction of T cell anergy and suppression of activities mediated by LAG3+ regulatory T cells (Tregs) are intriguing [40], given that Tregs are strongly implicated in T1D etiopathogenesis [41] and extensively investigated as therapeutic targets to ameliorate islet autoimmunity of T1D [42].…”

“…given that Tregs are strongly implicated in T1D etiopathogenesis [41] and extensively investigated as therapeutic targets to ameliorate islet autoimmunity of T1D [42].…”

The Multifactorial Progression from the Islet Autoimmunity to Type 1 Diabetes in Children

“…Both subsets of FOXP3-positive Tregs can inhibit and downregulate effector T cell proliferation and cytokine production and play a critical role in preventing autoimmunity [ 183 , 184 ]. Repairing the defects in Treg in order to restore the defects in immune system regulation is a potential strategy for disease treatment [ 185 ].…”