Can We Learn from Viruses How to Prevent Type 1 Diabetes? : The Role
of Viral Infections in the Pathogenesis of Type 1 Diabetes and the
Development of Novel Combination Therapies
Matthias von Herrath

Abstract
We will take a journey from basic pathogenetic mechanisms elicited by viral infections that play a role in the development of type 1 diabetes to clinical interventions, where we will discuss novel combination therapies. The role of viral infections in the development of type 1 diabetes is a rather interesting topic because in experimental models viruses appear capable of both accelerating as well as decelerating the immunological processes leading to type 1 diabetes. Consequently, I will discuss some of the underlying mechanisms for each situation and consider methods to investigate the proposed dichotomy for the involvement of viruses in human type 1 diabetes.

Prevention of type 1 diabetes by infection supports the so-called "hygiene hypothesis." Interestingly, viruses invoke mechanisms that need to be exploited by novel combinatorial immune-based interventions, the first one being the elimination of autoaggressive T-cells attacking the â-cells, ultimately leading to their immediate but temporally limited amelioration. The other is the invigoration of regulatory T-cells (Tregs), which can mediate long-term tolerance to â-cell proteins in the pancreatic islets and draining lymph nodes. In combination, these two immune elements have the potential to permanently stop type 1 diabetes. It is my belief that only combination therapies will enable the permanent prevention and curing of type 1 diabetes.

Introduction
It is a great honor for me to receive this year's American Diabetes Association Outstanding Scientific Achievement Award, and I would like to express my sincere gratitude to my peers. What do we know about type 1 diabetes? Well, we can be pretty certain that it is an autoimmune disease. Data from partial pancreas transplants between monozygotic twins showed that the nondiabetic pancreas was rapidly destroyed following transplantation[1] and was accompanied by infiltration of the islets, called insulitis, which is indicative of a strong autoreactive response, in the affected diabetic twin who received the transplant. In addition, autoantibodies to
â-cell antigens precede the clinical onset of hyperglycemia and can predict the risk of developing diabetes.[2,3] It is, however, still unclear what causes this autoreactivity to begin with. In addition to a strong genetic component, environmental factors, such as viral infections, lifestyle, and nutrition, have been implicated.

One noteworthy and striking observation in human type 1 diabetes is that the degree of islet inflammation is rather mild, that is, only a small percentage of islets are affected, especially in comparison with animal models. Pipeleers and colleagues[4] found that only 34% of all islets in pre-diabetic patients are affected by insulitis, a percentage that increased to somewhat higher levels at the time of diabetes diagnosis. Although the pathogenetic implication of this low degree of inflammation is unclear, it might be important in understanding how viral infections, as an additional factor, might contribute to the disease process.

Thus, there are many open questions, some of which we will need to answer in order to cure this terrible disease. Usually, and this is also the case for our group, animal models are utilized to better understand these and other immunological processes in type 1 diabetes pathogenesis as well as to define novel interventions. However, translation of at least some of the findings to human type 1 diabetes has been frustrating and ineffective. In this presentation, I will touch on several of the aforementioned issues and delineate present and future strategies that could help improve our mechanistic understanding and translational successes.

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