Autoimmunity occurs due to a breakdown in immunological tolerance, leading to uncontrolled adaptive immune responses against self-tissues. There are an estimated 50 million Americans that suffer from autoimmunity, which encompasses 100+ different disorders, which collectively effect virtually every organ and tissue. With ~16% of the US population suffering from autoimmunity, in 2001, annual estimated costs for their treatment calculated were greater than $100 billion. While every autoimmune disease is associated with immune dysregulation, no universal treatments exist. This proposal aims to generate a novel, cost-effective, universal off-the-shelf adoptive cell therapy (ACT) that can be used to treat autoimmune disease by enhancing immunological tolerance. Our strategy is to harness the power of endogenous CD4+Foxp3+ T regulatory cells (Treg) to enhance immune tolerance thereby dampening immune responses to self-tissues. Treg suppress immune-mediated inflammatory responses making them a strong therapeutic target for the treatment of autoimmunity and other inflammatory diseases. In clinical trials, transiently increasing Treg numbers was deemed safe and showed some efficacy. However, Treg cellular therapy faces a number of challenges that need to be overcome. To that end, we propose capitalizing on our recent discovery of a new B cell subset that induces the proliferation of Treg. These B cells were named B cell IgDlow/- (BDL) because their expression of low/neg IgD is the defining characteristic used for their purification and study. BDL are distinct from all other B cells subsets and play an essential role in Treg homeostasis. We have conducted proof-of-concept studies that BDL could be genetically engineered to enhance and sustain Treg numbers long-term thereby attenuating the severity of inflammation. This proposal outlines a strategy to develop a first-of-its-kind ACT for the treatment of autoimmunity utilizing BDL regulatory mechanisms. Our ACT is designed to be off-the-shelf and able to be universally administered to any patient that could benefit from increased Treg-induced tolerance. This will not only transform how autoimmunity is treated, but will greatly reduce the cost of treatment.
Autoimmune diseases if uncontrolled can cause severe tissue damage and even death. We have recently discovered BDL, which is a novel B cell subset that attenuates the severity of inflammatory diseases by induction of CD4+Foxp3+ regulatory T cell proliferation. This application outlines a strategy to develop a universal first-of-its kind B cell-derived adoptive cell therapy for the treatment of autoimmunity.
