Von Herrath, Matthias G., MD
Il-21 is a key regulator of nod t1d development
General Research Subject: Type 1 Diabetes
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2009
Project End Date: June 30, 2013
This work will focus on the role of a protein factor, termed interleukin-21 (IL-21), whose levels increase as type 1 diabetes develops and progresses. We have found that mice that are irresponsive to this factor IL-21 are completely resistant to the development of type 1 diabetes. This indicates that the action of this factor is at a crucial step (or multiple) in disease etiology, and opens opportunity for targeted blockade of this factor in type 1 diabetes patients. Before human intervention studies are initiated, more preclinical information is needed to help estimating and anticipating to potential side-effects. This proposal aims at determining how the factor IL-21 influences autoreactive cells, the cells responsible for the destruction of insulin-producing beta-cells in the pancreas, and/or the cells that keep autoreactive T cells under control, called regulatory T cells. From this, we expect to translate crucial insights in the action of a factor with a critical role in the development of type 1 diabetes into working recommendations for type 1 diabetes therapies.
Mentor: Matthias Von Herrath, M.D. Postdoctoral Fellow: Tom Van Belle, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Type 1 diabetes occurs when cells from the immune system mistakenly start attacking the beta cells in the pancreas. With less of these insulin-producing beta cells, the pancreas can no longer provide sufficient amounts of insulin to control the blood sugar levels. At the center of this project are the lymphocytes of the immune system. One of the crucial approaches in preventing or curbing type 1 diabetes is to stop the 'bad behavior' of these lymphocytes. The receptor for interleukin-21 plays a very important role in this 'bad behavior', so we want to know how we can best target this.
At the moment, we do not know for sure whether the strongest effect of such intervention will be achieved at the preventive or curative stage. Our guess based on the data so far is that we have a good chance of blocking disease development when intervention is started at the late preventive stage (when auto-antibodies are found) or early after onset. At the preventive stage, the amount of auto-aggressive lymphocytes is still limited. This allows for lower treatment dose and thus less side effects. Later, pancreatic damage will be more severe and this can result in several scenarios. Working medication dose might be higher or a combination of several therapies might be needed. The role of this project in designing therapies will be to better understand how and when the crucial step involving interleukin-21 takes place in diabetes development.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project is based on the important observation that mice that would normally develop diabetes are protected from diabetes when the receptor for a growth factor, called interleukin-21, is deleted. This means that very important disease promoting events go via this receptor. Finding ways to put a stopper on this bottleneck in the autoimmune process might give us therapies that can prevent or even fight diabetes. But there is more. The other thing we can learn from this project is which cells need to 'see' this growth factor at what phase of the disease process. Do cells need it early to become auto-aggressive, or do they need it late within the pancreas to kill the beta-cell? Does one cell type act as provider, and is another other the recipient? The answers to these questions will allow us to zoom in on the time frame and cell type to target once we have working 'stoppers' to this growth factor. Doing so will give much better targeted therapies with much less side-effects.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have a longstanding history in diabetes research and I continue to stay very involved in type 1 diabetes research for several reasons. Being an M.D. as well as a researcher, contributing to fight against the up-rise in T1D prevalence in the developed world is something I feel strongly about. From a research standpoint, autoimmune diseases like T1D are as intriguing as they are complicated. But more importantly, we need to find treatments in the near future that can be used as an alternative to life-long insulin therapy to treat this chronic autoimmune disease.
Obtaining this award is very important for the smooth continuation of the research projects so we can keep on doing cutting edge research. It also allows me to mentor some of the best researchers. I find the interaction with motivated and brilliant minds very stimulating and crucial in the research process. Without grants like this, it would be a lot more difficult to attract these people and help them progress to become valuable leading researchers in the diabetes field.
In what direction do you see the future of diabetes research going?
Most of the diabetes research now is done at the pre-clinical level using animal models. In the very near future, this type of research will remain instrumental, mainly because of the lack of non-invasive procedures for human research and reliable biomarkers for disease development or reversal. For a conversion to human research to occur, a better fundamental understanding of all systems involved, whether immunological or endocrine, will be crucial. That a shift towards human research is required has become clear from some failed efforts to translate the fundamental insights and therapeutic interventions to diabetes in the clinic. To propel human diabetes research, we are starting up the Diabetes Center in San Diego, CA to achieve a solid integration of traditional research approaches with patient recruitment and follow-up. Such set up will give us the full scale of research tools and angles to fight type 1 diabetes.
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