Antigen-specific T cells in immunotherapy-associated acute kidney injury

Brigham And Women'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

Project Summary Kidney inflammation contributes to chronic kidney damage, fibrosis and end-stage kidney diseases. Adaptive immune responses are tightly regulated in kidney to prevent excessive inflammation and to maintain self- tolerance. However, infections and medications can break self-tolerance and trigger autoimmunity. Immunotherapy has become a standard therapy for many cancers, but it can cause autoimmune kidney adverse events, including acute kidney injury and glomerulonephritis. Acute interstitial nephritis is the most common immunotherapy-associated acute kidney injury, characterized by immune cell infiltration in kidney. Our group showed it affects 2-3% of the patients receiving immunotherapy, resulting in significantly increased mortality and risk of progression to chronic kidney disease. While immunotherapy-associated acute kidney injury responds to corticosteroids, non-specific immunosuppression also blunts the tumor immune response. Thus, understanding the mechanisms of immunotherapy-associated acute kidney injury and developing targeted therapies that uncouple tumor- and kidney-immune response is critical to improve patient outcomes. Our overall goal is to identify antigenic and immunological drivers of immunotherapy-associated kidney- immune response. Kidney-associated antigens have been identified as targets of autoimmune kidney diseases, such as in membranous nephropathy and podocytopathies. Our data support that antigen-specific T cells also play a critical role in immunotherapy-associated acute kidney injury. Immune cell phenotype and tissue microenvironment are key determinants of inflammation: abundance of effector T cells among kidney- infiltrating lymphocytes is associated with severe kidney inflammation, whereas regulatory T cells (Treg) are associated with tolerance. Inflammatory tissue microenvironment and chemokines are key drivers of lymphocyte trafficking to kidney. However, detailed mechanisms to control effector T cells, Treg and kidney tissue microenvironment in immunotherapy-associated acute kidney injury is not well understood. This project aims to understand the roles of antigen-specific effector T cells (Aim 1), regulatory T cells (Aim 2) and kidney tissue microenvironment (Aim 3) in immunotherapy-associated acute kidney injury, using our novel mouse model, which expresses a series of model antigens in a kidney tubule-specific manner. This unique model will provide an ideal platform to delineate the phenotype and function of antigen-specific T cells in immunotherapy- associated acute kidney injury. By using novel, innovative approaches to study antigen-specific immune response in immunotherapy-associated acute kidney injury, we will better understand the mechanisms of immunotherapy-associated acute kidney injury, and will identify novel therapeutic targets for immunotherapy- associated acute kidney injury. This project will ultimately advance our fundamental knowledge of kidney immunobiology and bring new insights into the mechanisms of other forms of autoimmune kidney diseases.