Immunotherapy for the Prevention and Treatment of Type 1 Diabetes
Optimizing the path from bench to bedside
- Damien Bresson, PHD and
- Matthias von Herrath, MD
- From the Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California.
- Corresponding author: Matthias von Herrath, matthias{at}liai.org.
Type 1 diabetes is an autoimmune disease that causes the body to destroy insulin-producing β-cells in the pancreas. Genetic susceptibility is a major component of the disease pathogenesis. Many of the genes involved in disease susceptibility are major players in coordinating immune response. For example, the major histocompatibility complex (MHC) class II genes, known as human leukocyte antigens (HLAs) in humans, are the most prominent susceptibility genes (1). Besides genetic factors, there is strong evidence suggesting that environment contributes to the development of type 1 diabetes (2). The most striking example being that the incidence of diabetes differs in monozygotic twins (3). Other examples include the geographic distribution of type 1 diabetes and immigrants exhibiting the incidence prevalent in their new country of residence (4). Even if it may be a difficult task, efforts to find environmental causes are necessary as part of a potential future prevention program (5).
In humans, the accumulation of islet antibodies with differential specificities for β-cell proteins, in combination with genotyping for susceptibility alleles, can predict the risk to develop clinical diabetes. However, we are still unable to arrest β-cell destruction in pre-diabetic patients, even though a lot of evidence collected from preclinical studies using various therapeutic regimens in different animal models for type 1 diabetes has been successful in preventing type 1 diabetes (6). Some compounds (anti-CD3 antibodies, GAD of 65 kDa [GAD65], Diapep277, and anti-thymocyte globulin [ATG]) that reestablished long-term tolerance in animal models after new-onset type 1 diabetes show promising effects in reducing β-cell decline in phase I and II clinical trials in humans with recently diagnosed type 1 diabetes, but none of them was able to cure the disease (7). We have to ask, what are the current hurdles that make translation from animal models to humans so difficult and …
