New potential treatments for protection of pancreatic B‐cell function in Type 1 diabetes

Abstract

Type 1 diabetes mellitus results from the progressive and specific autoimmune destruction of insulin-secreting pancreatic B-cells, which develops over a period of years and continues after the initial clinical presentation. The ultimate goal of therapeutic intervention is prevention or reversal of the disease by the arrest of autoimmunity and by preservation/restoration of B-cell mass and function. Recent clinical trials of antigen-specific or non-specific immune therapies have proved that modulation of islet specific autoimmunity in humans and prevention of insulin secretion loss in the short term after the onset of disease is achievable. The identification of suitable candidates for therapy, appropriate dosage and timing, specificity of intervention and the side-effect profile are crucial for the success of any approach. Considering the complexity of the disease, it is likely that a rationally designed approach of combined immune-based therapies that target suppression of B-cell specific autoreactivity and maintenance of immune tolerance, coupled with islet regeneration or replacement of the destroyed B-cell mass, will prove to be most effective in causing remission/reversal of disease in a durable fashion.

Intradermal α1-antitrypsin therapy avoids fatal anaphylaxis, prevents type 1 diabetes and reverses hyperglycaemia in the NOD mouse model of the disease

“…Due to the pathogenic complexity of this disease, development of an effective method for late prevention or reversal post-onset of the disorder has been remarkably challenging [1]. Although recent studies have shown promising results in terms of reversing type 1 diabetes, many of these treatments can lead to detrimental side effects [2][3][4]. As such, the exploration of therapies with more tolerable adverse event profiles is urgently needed.…”

The role of the physician–scientist in bridging basic and clinical research in type 1 diabetes

“…Although in some patients, these therapies could induce clinical remission (i.e., relinquish the need for exogenous insulin), this effect was only transient, and lasting, at most, until near time when therapy was stopped. Although these therapies are considered too toxic for an indefinite use in those with newly diagnosed type 1 diabetes (especially young children), these studies did provide a proof-in-principle that if potent, yet safe and well tolerated, immune modulatory therapy was started soon after initial diagnosis, enough residual b-cells could be rescued to allow permanent reversal (or cure) of this disease [9,30].…”

“…Realizing that type 1 diabetes is an immune-mediated disorder, in the 1980s and 1990s, several clinical studies [9,30,[42][43][44][45][46][47] investigated the effect of potent immune Type 1 diabetes research Rigby 133 suppressants, including cyclosporine, azathioprine, prednisone and antithymocyte globulin, on newly diagnosed diabetes. Although in some patients, these therapies could induce clinical remission (i.e., relinquish the need for exogenous insulin), this effect was only transient, and lasting, at most, until near time when therapy was stopped.…”

Autoimmune diabetic patients undergoing allogeneic islet transplantation: are we ready for a regulatory T-cell therapy?

“…and non-calcineurin inhibitors (e.g., rapamycin, MMF, etc.) seem indispensable at this stage [81]. 3.…”