Immunotherapy on Trial for New-Onset Type 1 Diabetes

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Type 1 diabetes mellitus is an autoimmune disease in which pathologic, autoreactive T cells of the immune system attack the insulin-secreting pancreatic islets of Langerhans. Cytotoxic T cells, which bear the CD8 protein on their membrane, kill islets, thereby leading to lifelong dependence on insulin for affected patients. Over time, poorly controlled blood glucose levels inevitably result in early illness and early death.1 Invasive blood glucose monitoring, insulin administration, and medical complications of treatment can also themselves cause illness, despite decreased glycemia.

Immunosuppressive agents, one of the mainstays of approved treatments for transplantation, have been explored as therapy for patients with new-onset diabetes. Such agents ordinarily have widespread effects on immune function, leaving children and adults vulnerable to opportunistic infections and other adverse effects. The adverse effects in children sometimes outweigh the benefits, as was learned in clinical trials of the immunosuppressive drug cyclosporine for new-onset diabetes.2,3,4 Cyclosporine, a calcineurin inhibitor that lacks immune specificity, succeeded in reducing insulin requirements but had serious adverse effects, particularly nephrotoxicity. Another, more recent trial used intravenous anti-CD3 monoclonal antibodies for new-onset diabetes5,6; although promising in that it decreased the insulin requirement for a period after disease onset, the use of anti-CD3 monoclonal antibodies is also accompanied by adverse events, although substantially fewer to date than seen with cyclosporine. Consequently, researchers have sought to identify new, more targeted, and, ideally, preventive treatments aimed at new-onset type 1 diabetes in children. But most previously tested immune therapies for new-onset disease — including oral insulin, Q fever vaccine, methotrexate, and antithymocyte globulin, among others — have shown no or minimal therapeutic benefit.7

In this issue of the Journal, Ludvigsson et al.8 describe a randomized, controlled clinical trial involving children with new-onset type 1 diabetes to examine the safety and efficacy of immunotherapy with the recombinant human 65-kD isoform of glutamic acid decarboxylase (GAD) in a standard vaccine formulation with alum (GAD-alum) (ClinicalTrials.gov number, NCT00435981 [ClinicalTrials.gov] ). GAD-alum was given to children 10 to less than 18 years of age who had recent-onset disease; daily doses of insulin were given concurrently. The authors selected GAD for targeted therapy because this autoantigen, when used alone in prehyperglycemic mice, could prevent or slow the progression to hyperglycemia.9,10

GAD is a naturally occurring protein found in the brain and in insulin-secreting islets of the pancreas. It is a self protein that functions as an autoantigen in patients with type 1 diabetes or stiff-person syndrome, a disabling neurologic condition.11 In those with type 1 diabetes, self proteins can be subject to attack not only by autoreactive T cells but also by autoantibodies to GAD and a variety of other self proteins, such as the insulinoma-associated–2 autoantibody (IA-2), insulin autoantibody (IAA), and islet-specific glucose-6-phosphatase–related protein (IGRP), among others.12

The abnormal generation of cytotoxic T cells against these self proteins is probably due to defects in the capacity of so-called educator immune cells (e.g., dendritic cells and macrophages) to present the full repertoire of self peptides to newly forming T cells.13 Educator cells must present thousands of self proteins to prevent the escape of any cytotoxic, autoreactive T cells into the circulation (Figure 1). Failure to complete this self-antigen education leads to the release of autoreactive T cells and the generation of diverse autoantibodies against self proteins, often after the attacked islet tissue releases its contents. Autoimmunity may also be associated with the failure to generate regulatory T cells, whose role is to keep the immune system in balance, even where there may be rogue cytotoxic T cells that could be prevented from killing by these regulatory cells. In contrast, normal education of self proteins at lymphatic sites destroys autoreactive T cells before newly generated T cells are released from the bone marrow or thymus into the bloodstream (Figure 1).13