Brusko, Todd Michael, PhD
Influence of IL-12 and IL-18 on immunoregulation and type 1 diabetes pathogenesis
General Research Subject: Type 1 Diabetes
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Diabetes Type: Type 1 diabetes
Avoidance of infection and autoimmunity relies on a series of carefully orchestrated events within the immune system. When these processes fail, a variety of autoimmune disorders can arise, including type 1 diabetes (T1D) which occurs when insulin producing pancreatic beta cells are destroyed. One key constituent charged with the responsibility to control such processes are a unique white blood cell referred to as Helper T (Th) cell. A number of studies suggests that Th cells from patients with T1D exhibit a remarkable loss of immune regulation. We believe the reason for this loss of control resides, in part, in the abnormal production of inflammatory products of immune sentinel cells, referred to as antigen presenting cells that produce the factors IL-12 and IL-18.
In this application, we are proposing to determine how these factors (cytokines) are controlled during the development of T1D. Moreover, we will determine how they influence the populations of Th cells that either drive the destruction of pancreatic beta cells, or control these immune responses through the activity of regulatory T cells. Additionally, we seek to identify the genetic basis for the aforementioned defects. The successful completion of these aims is expected to better identify individuals at risk for T1D who may go on to develop the disease. Additionally, we expect to identify specific opportunities to target these cytokines and intervene in the disease process, potentially halting T1D progression or setting the stage for beta cell replacement therapies.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The research efforts of this project address the fundamental question of "how" diabetes is initiated. We believe inflammation is a critical component of the disease process. In this project, we will study two chemical inflammatory messengers of the immune system (IL-12 and IL-18) and seek to understand how they influence the immune response. Another important component of this project involves understanding how specific genes contribute to susceptibility to disease. Ultimately, this project aims to understand how genetic variation influences immune responses that lead to type 1 diabetes.
Identifying pathways that initiate inflammation and beta cell destruction provide a target for therapeutic intervention. Moreover, by understanding the genetic origin of immune system defects, it may allow future clinical trials to be tailored to individual patients that harbor very specific defects.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Type 1 diabetes is a disease initiated by immune inflammation and related tissue destruction. By understanding the specific cell populations and chemical messengers involved, we gain the ability to block these damaging signals during the disease process leading to either a prevention prior to onset, or a cure when sufficient beta cell mass is restored.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I made a decision very early on in my career to focus almost exclusively on type 1 diabetes research. My scientific passion involves understanding how the immune system makes a decision between immune tolerance (non-responsiveness to self-tissues) and autoimmunity. I address this fundamental question (and personal passion) in the context of type 1 diabetes with the hope of finding ways to restore immune tolerance in individuals who develop the disease.
The research program in the Brusko Laboratory focuses on studying the human immune response in individuals that develop autoimmunity in an effort to develop better ways to predict, intervene, and ultimately treat individuals with type 1 diabetes. The laboratory is particularly interested in the fundamental events that control T cell activation and expansion, as these events are defective in individuals that develop type 1 diabetes. The studies supported by the ADA are focused on identifying the genetic factors that lead to a breakdown in the mechanisms that maintain immune tolerance. These studies focus on a susceptibility gene (IL18RAP) that may contribute to defects in both the innate and adaptive immune responses in patients with T1D. The goal of these studies is to develop targeted therapies in an effort to correct specific defects in pathways that lead to disease.
In what direction do you see the future of diabetes research going?
I believe the previous decade was characterized by studies seeking to identify the genes that confer susceptibility to disease. I believe strongly that the following decade will be focused on identifying how those gene variants alter the immune response. This knowledge will ultimately be used to design more efficacious therapies based on a patient's own genetic profile.
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