Therapy with GAD in diabetes

Abstract

The enzyme glutamic acid decarboxylase (GAD) is of great importance for the neurotransmission in the central nervous system, and therefore of interest for treatment of pain and neurological disease. However, it is also released in pancreas although its role is not quite clear. GAD is a major auto-antigen in the process leading to type 1 diabetes with both a clear cell-mediated immune response to GAD and auto-antibodies to GAD (GADA), which can be used as a predictor of diabetes. Administration of the isoform GAD65 can prevent autoimmune destruction of pancreatic beta cells in non-obese diabetic (NOD) mice and the subsequent need for exogenous insulin replacement. In Phase I and II studies an alum-formulated vaccine (Diamyd) has shown to be safe, and in a dose-finding study in Latent Autoimmune Diabetes in Adults (LADA) patients 20-microg was given subcutaneously one month apart indicating preservation of residual insulin secretion. A double-blind randomized Phase II trial in 70 patients (10-18 years old) with recent-onset type 1 diabetes showed significant preservation of residual insulin secretion and a GAD-specific immune response, both humoral and cell-mediated, but no treatment-related adverse events. With this promising background further studies are on their way, both intervention in newly diagnosed type 1 diabetic patients, and trials to prevent the disease.

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

“…Moreover, the elimination of protease cleavage sites within a protein in order to avoid the generation of intermediates results in less toxicity in mice [109]. The success of antigen-based treatments for autoimmunity might depend on the dose administered, leading to T cell regulation and tolerance [110].…”

Antigen-specific immunotherapy and influenza vaccination in type 1 diabetes: timing is everything

“…Alum was selected as an adjuvant for GAD in order to steer away from a Th1-dominated, proinflammatory cellular autoimmune response towards a Th2 response, which favours humoral immunity (antibody production) [10]. Tavira et al demonstrated that individuals who received the influenza vaccination within close proximity of GAD-alum treatment had increased secretion of GAD-induced proinflammatory cytokines, such as IFN-γ and TNF-α, compared with those who received the vaccine further from GAD-alum therapy [5].…”

Antigen-based vs. systemic immunomodulation in type 1 diabetes

“…These include a role for GAD as a possible regulator of pancreatic hormone release, a paracrine signal molecule between endocrine cells in the pancreatic islets or a negative regulator of first-phase insulin secretion. 122 To make it even more complex, this enzyme consists of two isoforms, GAD65 and GAD67 (65 kDa and 67 kDa respectively). 123 Interestingly, several studies already demonstrated a therapeutic capacity of GAD65 in experimental T1D9 models.…”

“…This conventional adjuvant was chosen because it stimulates a humoral Th2 (T-helper 2) response rather than a cellular pathogenic immune response. 122 A phase two dose-titration study (Subcutaneous GAD65) was designed to assess the general safety profile of GAD-Alum and its possible toxic effect on β-cells.…”