Understanding the genetic and immunologic basis of autoimmune hemolytic anemia (AIHA) in a novel canine model system

Project Summary/Abstract Autoimmune hemolytic anemia (AIHA) is a severe hematologic disorder caused by the antibody-mediated destruction of red blood cells (RBCs). The disease causes significant morbidity and mortality for patients: With today's treatments, patients face a significant risk of death, high relapse rates, and only a rare chance at full remission. Better therapies are possible, but our limited understanding of the genetic and immunologic mechanisms that lead to AIHA are roadblocks to making new treatments a reality. Fortunately, dogs provide an exceptional naturally occurring model for studying genetic risk factors and T cell biology in AIHA. The disease is naturally occurring in both humans and dogs, and shares similar clinical, genetic, and immunologic underpinnings in both species – while occurring significantly more frequently in dogs compared to humans. The goal of this study is to lay the groundwork for a canine model system to study AIHA by identifying genetic risk factors for the disease and by characterizing the autoreactive T cell population in two highly predisposed dog breeds. Specifically, we will test the hypothesis that we will identify multiple genetic risk variants affecting humoral immunity, along with autoreactive CD4+ T cells that are activated by peptides derived from RBC surface antigens. Once we identify genetically predisposed dogs and the T cell epitopes that trigger AIHA, we can begin to develop and test approaches that manipulate or downregulate the aberrant immune response in highly predisposed animals. Ultimately, we expect to use this canine model system to drive advances in our understanding of AIHA and foster the development of novel immunotherapies for humans. The work proposed in this application will be completed by a highly collaborative team of scientists anchored at the renowned Center for Immunology at the University of Minnesota Medical School, the University Minnesota College of Veterinary Medicine, and the University of Georgia College of Veterinary Medicine.