News & Research

    The University of Florida, Gainsville, Florida

The T1D-resistance linkage Idd22 controls beta cell resistance to autoimmune destruction

General Research Subject: Type 1 Diabetes

Focus: Genetics\Type 1 Diabetes, Immunology, Islet Biology\Apoptosis

Type of Grant: Basic Science

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Diabetes Type: Type 1 diabetes

Research Description

The genetics of susceptibility versus resistance to autoimmune T1D has primarily focused attention on candidate genes controlling function of the immune system rather than on the target beta cell.  The assumption has been that insulin producing beta cells express a common repertoire of target antigens, yet play no other role in T1D pathogenesis than the corpse.  In contrast to this commonly held view, our work has clearly shown that genetics play an important role in resistance of the target tissue to the autoimmune destruction leading to Type 1 Diabetes.  The current proposal exploits a genetic region that provides strong resistance to autoimmune-mediated destruction by bolstering beta cell self-defenses.  The goals of this proposal are to identify the gene responsible for this unique resistance and determine the mechanism where by this gene acts to prevent beta cell death.  Protective factors pancreatic islets can employ to ward off autoimmune effector mechanisms have important ramifications for transplantation, stem cell engineering, and future genetic as well as pharmacological diabetes preventative therapies.

Research Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

The objective of this proposal is to use the unique ALR mouse strain to better understand genetic mechanisms that protected beta cells from autoimmune destruction. The NOD-related ALR mouse strain, selected for resistance to alloxan free radical-induced diabetes, maintains a stronger systemic ability to inactivate toxic free radicals, extending to the pancreatic islet level.  This dominantly inherited heightened defense is of great significance to diabetes researchers because pancreatic islets exhibit lower defenses (and greater sensitivity) to oxidative damage compared to other tissues.  In contrast to control strains, ALR islets show incredible resistance to destruction by alloxan, peroxide, and to immune-mediated injury, including that produced by combinations of proinflammatory cytokines and NOD derived cytotoxic T lymphocytes. 

Genetic dissection of these ALR derived phenotypes has demonstrated that the increase beta cell defenses and resistance to lysis by autoreative and diabetogenic cytotoxic T lymphocytes map to the ALR-derived Idd22 locus on mouse Chromosome 8 (Chr. 8).  This proposal seeks to define how the Idd22 linkage heightens the basal stress response and the role of the heightened defense plays in diffusing the pathways used by immune effectors to destroy beta cells.  The biochemical and molecular differences elucidated between ALR and controls will be exploited to understand the genetic factor on Chr. 8 controlling this unusual protection. These mechanisms can be exploited to protect the residual beta cell mass in at risk individuals or persons with type 1 diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

The genetics of autoimmune diabetes has primarily focused attention on candidate genes controlling aberrant immune responses rather than on the target beta cell.  The assumption has been that insulin producing beta cells express a common repertoire of target antigens, yet play no other role in T1D pathogenesis than the corpse.  In contrast to this commonly held view, our work has clearly shown that genetics play an important role in resistance of the target tissue to the autoimmune destruction leading to Type 1 Diabetes. The current proposal exploits a genetic region that provides strong resistance to autoimmune-mediated destruction by bolstering beta cell self-defenses.  The goals of this proposal are to identify the gene responsible for this unique resistance and determine the mechanism where by this gene acts to prevent beta cell death. Protective factors pancreatic islets can employ to ward off autoimmune effector mechanisms have important ramifications for transplantation, stem cell engineering, and future genetic as well as pharmacological diabetes preventative therapies.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?  

Diabetes is a significant health concern for the US.  However, many of us have personal vendetta and a significant reason for my involvement in diabetes research is my family history of the disease.  

Since 1997 I have been focused on the hypothesis that factors at the beta cell level contribute to the onset of T1D.  There are currently three central projects in my laboratory.  This is one of the three.  In addition there is significant synergism of this project with the other two projects.  Therefore this project is a centerpiece of my lab's focus.

In what direction do you see the future of diabetes research going?

Immune regulation represents only one half of the equation for any therapy to successfully cure autoimmune type 1 diabetes.  The second involves ß cell viability and proliferation.  Although detailed information about the relative balance of ß cell proliferation and death in pancreata from subjects with T1D is not minimal, recent metabolic data from new onset T1D patients, as well as autopsy data collected from pancreata of those with T1D suggests that the quantity of ß cell mass is low and significantly damaged. 

Not surprisingly, the progressive deterioration in ß cell function that accompanies T1D has sparked interest in identifying factors that either promote formation of new ß cells or inhibit the death of vulnerable ß cells.  Hence, administration of agents influencing either of these two areas may allow for expansion and recovery of ß cell mass, ultimately leading to increased insulin secretion and improved glycemic control.  This proposal will identify a gene that can likely protect beta cells from autoimmune destruction and in doing so will provide a possible therapeutic target to be used in combination with an immunoregulatory regimen in future diabetes preventative/reversal strategies.