Abstract
Islet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease that results from T cell-mediated destruction of pancreatic beta cells
To further delineate the transient nature of global B cell depletion observed in rituximab trials, Serreze and colleagues used human and murine anti-CD20 as a B lymphocyte depleting agent in non-obese diabetic (NOD) mouse models to demonstrate that B lymphocytes downregulate CD20 upon entry into the islet, which impedes the capacity for anti-CD20 treatment to affect disease at later stages [26]
Insulin is a major autoantigen in type 1 diabetes (T1D): insulin autoantibodies (IAAs) signal that pathogenic T-B interactions have occurred and predict T1D in both mice and humans [28,29,30]
Summary
Citation: Felton, J.L.; Conway, H.; Department of Pediatrics, Division of Pediatric Endocrinology and the Herman B. Wells Center for Pediatric Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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