- Assist. Prof. Mandy Ford, Principal Investigator
- Dr Scott Krummey, Research Assistant
- Assist. Prof. Andrew Adams, Collaborator
- Assist. Prof. Alton Farris, Collaborator
- Emory University, Atlanta, USA
- Targeting Recently Identified T Cell Subsets using Novel Immunosuppression
Belatacept was recently approved by the FDA and is a new drug in the armamentarium of therapeutics to prevent transplant rejection. It is one of a new class of immunosuppressants that have the potential to inhibit anti-graft immune responses following transplantation with limited off-target toxicities compared to current standard-of-care regimens. Side effects of current immunosuppressive drugs include impaired kidney function, diabetes, high cholesterol and triglycerides, and increased risk of cardiovascular disease. While the benefit of diminished side effects have made it an attractive alternative to current standard-of-care immunosuppression, its implementation in clinical transplantation has been marked by an increased rate of acute rejection in both kidney and liver transplant recipients. Given its kidney and cardiac benefits, understanding the mechanisms by which, in a subset of recipients, belatacept fails to protect grafts from rejection is paramount to optimizing this strategy for clinical use in both renal and liver transplantation. In dissecting the mechanisms underlying this belatacept-resistant rejection, our preliminary studies in vitro have revealed that a recently discovered subset of CD4+ T cells exhibit markedly increased resistance to belatacept. This subset of CD4+ T cells is highly inflammatory and is characterized by secretion of a potent inflammatory mediator termed interleukin-17 (IL-17). In a small pilot cohort of belatacept-treated renal transplant recipients experiencing acute rejection, we observed a significant increase IL-17-secreting CD4+ T cells in the blood, compared to patients experiencing acute rejection that were treated with standard-of-care immunosuppression. Thus, we hypothesize that Th17 cells play a critical role in belatacept-resistant rejection. The overarching goal of this proposal is to test this hypothesis and to explore the cellular and molecular pathways that control the activation of IL-17-secreting cells during transplantation.