Serreze, David V.
Dendritic cell therapies for autoimmune diabetes
General Research Subject: Type 1 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Genetics\Type 1 Diabetes, Immunology
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Type-1 diabetes (T1D) is an autoimmune disease in which T-lymphocytes mistakenly destroy insulin producing pancreatic beta-cells. Normally, a subset of another immune cell population called dendritic cells (DC) mature to a 'tolerogenic' state that blocks development of autoreactive T-cells. A failure to generate such tolerogenic DC contributes to T1D development in the NOD mouse model. In turn, the diminished development of tolerogenic DC in NOD mice results from defective activity of another immunological-regulatory population called NKT-cells. Treatment with a drug called GalCer restores the ability of NKT-cells to drive production of T1D protective DC in NOD mice. However, GalCer treatment of normally disease resistant B6.H2g7 mice causes their DC to mature to a state actually promoting rather than inhibiting T1D development. Hence, while the induction of NKT-matured DC might be considered a T1D intervention in humans, there may be an unknown proportion of individuals in which it should not be attempted. Thus, our first aim is to determine the subset and functional characteristics of the NKT-matured DC respectively inhibiting or promoting T1D development in NOD and B6.H2g7 mice. Aim 2 is to determine the genetic basis for such differences in NKT-driven DC maturation responses. Such studies may ultimately allow development of predictive tests that can identify humans at future T1D risk in which NKT-driven DC maturation should or should not be considered as a possible disease intervention approach.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our laboratory is focused on the use of mouse models to dissect the genetic basis for development of the aberrant autoimmune responses that causes type 1 diabetes (T1D) by destroying insulin producing pancreatic ß-cells. A type of white blood cell called T-lymphocytes ultimately mediates the autoimmune destruction of pancreatic ß-cells during T1D development. However, it is through interactions with another class of white blood cells called dendritic cells (DC) that T-lymphocytes normally receive instructional information on how to distinguish between invading infectious agents and the body's own cell types. We have found some of the genes contributing to T1D development in the NOD mouse model do so by limiting the ability of DC to mature to a point where they can educate T-cells not to recognize and destroy pancreatic ß-cells. This ADA sponsored project is focused on learning more about how genes contributing to T1D development by impairing the maturation of DC capable of preventing autoreactive T-lymphocyte responses functionally do so, and assessing whether this defect might be corrected by certain pharmacological interventions. These studies may ultimately contribute to an improved capacity to identify humans at future risk for T1D development, and also provide insights to possible means that would block disease progression in such individuals.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our work might identify means that would block the autoreactive T-cell responses that cause T1D. This could ultimately allow for the reversal of T1D by the transplantation of pancreatic islets.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My now over 26 year effort to unravel the genetic basis of T1D is largely driven by firsthand knowledge of how this usual childhood onset disease can not only have devastating effects for patients, but also their families. It is my hope that this ADA sponsored research will contribute to an ultimate arrival of a day when it will be possible to accurately predict children at future T1D risk, and initiate a disease preventative pharmacological intervention. If you can prevent, you never have to cure.
In what direction do you see the future of diabetes research going?
It will be important to utilize combined genetic, metabolic, and
immunological profiling approaches to gain a future capacity to identify
humans at future risk for T1D at earlier points of disease development
than now possible. This will be important since animal model studies
indicate that possible clinically applicable T1D intervention approaches
are most effective when initiated at the earliest stage of disease
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