Immune interventions to preserve β cell function in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to destruction of pancreatic beta cells, lifelong dependence on insulin, and increased morbidity and mortality from diabetes-related complications. Preservation of residual beta cells at diagnosis is a major goal because higher levels of endogenous insulin secretion are associated with better short- and long-term outcomes. Over the past 3 decades, a variety of immune interventions have been evaluated in the setting of new-onset T1D, including nonspecific immunosuppression, pathway-specific immune modulation, antigen-specific therapies, and cellular therapies. To date, no single intervention has produced durable remission off-therapy in the majority of treated patients, but the field has gained valuable insights into disease mechanisms and potential immunologic correlates of success. In particular, T cell-directed therapies, including therapies that lead to partial depletion or modulation of effector T (Teff) cells and preservation or augmentation of regulatory T (Treg) cells, have shown the most success and will likely form the backbone of future approaches. The next phase will see evaluation of rational combinations, comprising one or more of the following: a Teff-depleting or modulating drug, a cytokine-based tolerogenic (Treg-promoting) agent, and an antigen-specific component. The long-term goal is to reestablish immunologic tolerance to beta cells, thereby preserving residual beta cells early after diagnosis or enabling restoration of beta cell mass from autologous stem cells or induced neogenesis in patients with established T1D.

Correlation Among Hypoglycemia, Glycemic Variability, and C-Peptide Preservation After Alefacept Therapy in Patients with Type 1 Diabetes Mellitus: Analysis of Data from the Immune Tolerance Network T1DAL Trial

“…31 Even though the remaining β-cell mass at diagnosis may constitute only 20% or less of the original, pre-disease mass, accumulating evidence from the DCCT and other studies indicates that even modest amounts of endogenous insulin production substantially improve short- and long-term outcomes in these patients. 17, 18, 20 It is known that the rate of decline of β-cell function after diagnosis in T1D is highly variable and many patients retain detectable insulin secretion (as measured by stimulated C-peptide production) for years or decades.…”

“…Therapies that have shown success in preserving C-peptide include drugs that target T cell frequency or function (anti-CD3 mAb, alefacept), costimulation blockade (CTLA4-Ig), inflammatory cytokines (anti-TNFα), and B cells (anti-CD20 mAb). 31 Mechanistically these agents are very different and efficacy may result from alterations in the balance between regulatory and effector T cells, induction of hyporesponsiveness in autoreactive T cells, or general anti-inflammatory effects. 31 One or more of these mechanisms could influence glucose metabolism – by affecting insulin sensitivity or glucose disposal rates – but in general this is not well understood.…”

Comment on: “Therapies to Preserve β-Cell Function in Type 1 Diabetes”

“…Of the eight clinical studies conducted over the past decade, including one in patients with adult-onset latent autoimmune diabetes (LADA), two showed no effect of vitamin D supplementation on RBCF [6,7], four showed a slower decline of RBCF [3,4,8,9], while two others showed a trend towards slower decline of RBCF that did not reach a statistical significance [10,11]. Nevertheless, many lessons have been learnt from these trials similar to the experience with other immune interventions in T1D [5]. In particular, issues…”

“…In addition to the several previously described mechanisms of its immunomodulation in T1D, recent evidence suggests that vitamin D increases the numbers as well as the functional capacity of regulatory T cells (Tregs), which are an important component of the process of b-cell destruction in T1D [3,4]. It is thought that the combined approaches for future evaluation will include an antigen-specific agent, effector T cell-depleting ormodulating drug, and a Tregs-promoting agent [5]. In this regard, vitamin D may be included as a Tregs-boosting agent in combination therapies for b-cell disease [2].…”

“…Easy availability, low cost of therapy and relatively lower toxicity as compared with other immune interventions make vitamin D a suitable component of combined therapies. While a number of studies in animal models have shown promising effects of vitamin D on insulin secretion and insulin sensitivity, the results of clinical trials in patients with T1D have been far less impressive [2,5]. Of the eight clinical studies conducted over the past decade, including one in patients with adult-onset latent autoimmune diabetes (LADA), two showed no effect of vitamin D supplementation on RBCF [6,7], four showed a slower decline of RBCF [3,4,8,9], while two others showed a trend towards slower decline of RBCF that did not reach a statistical significance [10,11].…”