Center for Immunology Faculty Highlight: Brian Fife Receives Three NIH Awards to Study Autoimmune Diabetes

The Center for Immunology (CFI) is pleased to highlight new NIH-supported research awards to CFI faculty investigating fundamental mechanisms of immunity, inflammation, and autoimmune disease.

Brian Fife Receives Two NIH R01 Awards and One R21 Award to Study Autoimmune Diabetes

CFI faculty member Dr. Brian Fife has been awarded two new NIH R01 grants and one R21 grant to investigate the mechanisms of immune tolerance and autoimmune disease, with a specific focus on Type 1 Diabetes (T1D).

The awards include:

• NIH/NIDDK R01 (1R01DK144460): "Engineering Tregs for Autoimmune Diabetes Therapy"
• NIH/NIAID R01 (1R01AI195876): "Determine How a Normal Microbial Environment Protects Against Autoimmune Diabetes"
• NIH/NIAID R21 (1R21AI196624): "Generation and Validation of Peptide I Restricted CAR Tregs"

Together, these three grants focus on understanding the mechanisms that maintain immune tolerance and applying that knowledge toward the treatment and prevention of autoimmune disease, specifically Type 1 Diabetes.

Engineering Regulatory T Cells for Autoimmune Diabetes Therapy

T1D is an autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic beta cells, significantly impacting human health. Under normal conditions, tolerance to beta cells is maintained in part by regulatory T cells (Tregs). In T1D, Tregs fail to adequately protect beta cells, leaving them vulnerable to immune attack.

Dr. Fife's first R01 project addresses this challenge by creating "designer" Tregs engineered for islet antigen specificity and directed toward diabetes-relevant MHC class II targets. If successful, this technology could lead to more personalized and effective immunotherapies for T1D.

Related to this approach is the R21 project, which will develop and harness MHC class I monoclonal antibodies to generate chimeric antigen receptor (CAR) regulatory T cells. These engineered CAR Tregs will target MHC class I beta-cell-specific peptides that are thought to play an important role in T1D pathogenesis.

Understanding How the Microbial Environment Influences Autoimmune Diabetes

Dr. Fife's second R01 study focuses on the rising incidence of T1D, which is thought to be linked to early-life exposure to microbes, environmental pollutants, and diet.

Studies of viral infections in mouse models of diabetes have demonstrated that infections can either accelerate or protect against the development of diabetes. These differences can depend on factors such as the age at which infection occurs and the degree of pancreatic insulitis. An important factor in determining whether CD4+ T cells will prime the immune system to initiate T1D is the inflammatory context present during the initial encounter with peripheral antigen.

At the University of Minnesota, researchers at the Center for Immunology have developed a "dirty" mouse model that provides a more natural microbial environment in which to study how the immune system develops and responds to microbes and viral pathogens. Using this more physiological model, Dr. Fife's research will investigate how infections influence immunity and determine whether they ultimately trigger or protect against autoimmune disease.

Together, these three NIH-funded projects provide complementary approaches to understanding autoimmune diabetes—from engineering regulatory T cells to restore immune tolerance to investigating how environmental and microbial exposures shape susceptibility to disease.