Targeting the Neonatal Fc Receptor, FcRn, to Treat Autoimmunity and Elucidation of Sites of FcRn Function
type: CreativeWork
description: The neonatal Fc receptor, FcRn, is expressed in many different cell types and serves several functions, some of which are cell type-specific. A function common to most cell types that express this receptor is salvage of IgG from cellular degradation which is responsible for the long in vivo half-life of IgG. This property of IgG is responsible for its indispensable role in humoral immunity and also contributes to the successful use of IgGs as therapeutics. In autoimmunity, however, autoantibodies are generated that can contribute to pathology. FcRn-mediated salvage is also responsible for the long half-life of autoreactive IgGs. Therefore, this study employed an engineered antibody (Abdeg, a novel FcRn inhibitor) that lowers endogenous IgG levels by competing for binding to FcRn, to directly assess the effect of decreased antibody levels in an autoantibody-dependent murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Essentially, Abdeg delivery reduced the accumulation of autoantibodies in the target organs and ameliorated the disease. Autoreactive CD4+ T cells are also known to play an important role in the pathogenesis of autoimmune diseases. Thus, with the goal of inducing antigen-specific T cell tolerance, the current study employed immunoglobulin Fc engineering to develop a novel platform for the delivery of peptide epitopes as Fc-peptide fusions with different dynamic properties. Using very low doses of these engineered antigens to avoid anaphylactic shock, the study demonstrates that the longevity of the peptide antigen is the primary determinant of tolerance induction in a murine EAE model that is driven by autoreactive CD4+ T cells. Long-lived Fc-antigen fusions are effective tolerogens in both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Further, to identify the FcRn-expressing cell types that mediate the effects of Abdegs and Fc-antigen fusions on autoa…
abstract: The neonatal Fc receptor, FcRn, is expressed in many different cell types and serves several functions, some of which are cell type-specific. A function common to most cell types that express this receptor is salvage of IgG from cellular degradation which is responsible for the long in vivo half-life of IgG. This property of IgG is responsible for its indispensable role in humoral immunity and also contributes to the successful use of IgGs as therapeutics. In autoimmunity, however, autoantibodies are generated that can contribute to pathology. FcRn-mediated salvage is also responsible for the long half-life of autoreactive IgGs. Therefore, this study employed an engineered antibody (Abdeg, a novel FcRn inhibitor) that lowers endogenous IgG levels by competing for binding to FcRn, to directly assess the effect of decreased antibody levels in an autoantibody-dependent murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Essentially, Abdeg delivery reduced the accumulation of autoantibodies in the target organs and ameliorated the disease. Autoreactive CD4+ T cells are also known to play an important role in the pathogenesis of autoimmune diseases. Thus, with the goal of inducing antigen-specific T cell tolerance, the current study employed immunoglobulin Fc engineering to develop a novel platform for the delivery of peptide epitopes as Fc-peptide fusions with different dynamic properties. Using very low doses of these engineered antigens to avoid anaphylactic shock, the study demonstrates that the longevity of the peptide antigen is the primary determinant of tolerance induction in a murine EAE model that is driven by autoreactive CD4+ T cells. Long-lived Fc-antigen fusions are effective tolerogens in both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Further, to identify the FcRn-expressing cell types that mediate the effects of Abdegs and Fc-antigen fusions on autoa…
author: Challa, Dilip Kumar
language: en
keywords: Antibodies, Autoantibodies, Encephalomyelitis, Autoimmune, Experimental, Histocompatibility Antigens Class I, Immunoglobulin G, Protein Engineering, Receptors, Fc
date published: 2020-01-02T18:19:24Z
date modified: 2026-07-24T05:52:29Z
provider: University of Texas Southwestern Medical Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Texas Southwestern Medical Center

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2152.5/7727