Pathological autoimmunity occurs when the immune system attacks healthy tissue, causing immunopathology and tissue dysfunction. There are over 80 recognized autoimmune diseases that afflict 25-50 million Americans, and this represents a significant financial and public health burden. The experimental mouse has been a standard model of autoimmune research for several decades. However, although research in mice has led to most of the fundamental insights into the development and function of the mammalian immune system, restoration of self-tolerance has been relatively easy to achieve in mouse models of autoimmune disease and many of these findings have been difficult to translate into effective therapies for human autoimmunity. This is likely due to 1) Fundamental differences in immune pathways responsible for tolerance induction in mouse vs. human, and 2) Differences in the immune environment between carefully housed and monitored experimental mice and the more heterogeneous and daunting immune challenges faced by humans, who are exposed to continual acute and chronic infection along with an array of environmental exposures that can damage tissues and provoke immune reactions. This highlights the need to study immune tolerance in animal models that more closely resemble human immune systems, and account for each of these important factors. The goal of this proposal is to use novel and realistic mouse models that more closely mirror human immune function to study tolerance induction via manipulation of the IL-2/TR cells axis, and identify critical parameters that influence the outcome of therapies aimed at preventing or ameliorating autoimmune disease.

Public Health Relevance

Pathological autoimmunity occurs when the immune system attacks healthy tissue, causing immunopathology and tissue dysfunction. Although research in mice has led to most of the fundamental insights into the development and function of the mammalian immune system, restoration of self-tolerance has been relatively easy to achieve in mouse models of autoimmune disease and many of these findings have been difficult to translate into effective therapies for human autoimmunity. The goal of this proposal is to use novel and realistic mouse models that more closely mirror human immune function to study tolerance induction via manipulation of the IL-2/regulatory T cell axis, and identify critical parameters that influence the outcome of therapies aimed at preventing or ameliorating autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI136475-04
Application #
10062808
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Rothermel, Annette L
Project Start
2017-12-20
Project End
2022-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101