Pathobiology of ANCA Glomerulonephritis: Targeting Adaptive and Innate Immune Processes for Precision Therapies

点击翻译按钮获取中文摘要

ABSTRACT Anti-neutrophil cytoplasmic autoantibodies (ANCA) glomerulonephritis (GN) is a life-threatening autoimmune disease. While current immunosuppressive agents produce remission in the majority of patients, our treatment has had precision more akin to a chainsaw rather than a scalpel. The lack of specific, targeted immune therapy leaves patients with an overly handicapped immune system and a host of toxic side effects. Our proposal seeks to to finally advance the field toward more precise and targeted therapies with far less potential for harm. Building upon our prior body of work, we will attempt to exploit the adaptive autoimmune responses seen in ANCA GN as targets for immunomodulatory therapies by multiple approaches. By using our previously developed epitope mapping techniques, we will engineer chimeric autoantibody receptor (CAAR) T cells that will specifically target only those B cells that express the pathogenic ANCA antibody epitopes. In another approach, we will profile the heterogeneous population of T regulatory cells. After identifying those that are fully suppressive, we will attempt to expand this population in vitro and confirm that they retain their suppressive function. This work will determine whether in future studies, we can first harvest these cells from ANCA GN patients, expand them in vitro, and reintroduce them into patients to provide immunomodulatory effects that would reintroduce autoimmune tolerance. Utilizing our well-characterized mouse model of myeloperoxidase (MPO) ANCA GN, we will explore the mechanisms by which T (and B) regulatory cells suppress autoimmunity and leverage this knowledge to develop pre-clinical models of T regulatory cell therapy. In addition to the potential role of cell-based therapies, we will explore the role of the innate immune system in ANCA GN using our established MPO mouse model and novel models that we have developed of granulomatous disease. These models will also us to identify components of the innate immune response that may be amenable to novel therapies. Further, we will determine whether we can manipulate the epigenetic changes that alter expression of the autoantigen proteins targeted by the autoimmune processes that drive ANCA GN. These foundational studies have been designed with the intent to inform Investigative New Drug (IND) applications to the Food and Drug Administration (FDA). This work will usher in a new therapeutic era for ANCA GN, characterized by greater precision, less toxicity and perhaps, longer duration.