SHORT DESCRIPTION Use of AHR agonists to inhibit pathogenic Tfh/Tph cell differentiation, potentially reducing disease activity.
INVENTORS
* Principal Investigator
NU Tech ID: NU 2023-127
IP STATUS
US Patent pending
DEVELOPMENT STAGE
TRL-3 - Experimental Proof-of-Concept: Key functions have been demonstrated in controlled in vitro assays.
BACKGROUND
Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren disease, or systemic sclerosis occur when the immune system attacks the body's own tissues, driving chronic inflammation and organ damage. SLE affects roughly 204,000 Americans, and RA affects about 10.6 million U.S. adults, with a disproportionate burden on women and on Black, Hispanic, and Indigenous communities. A central driver of these diseases is overactive T cells and B cells that leads to the generation of harmful autoantibodies. Current treatment relies on broad immune suppression and immune-modifying drugs, including hydroxychloroquine, steroids, immunosuppressants, and newer biologic therapies such as belimumab and anifrolumab. While these therapies can control disease for some patients, many still experience ongoing disease activity, flares, or incomplete responses, and long‑term steroid and immunosuppressant exposure carries significant safety concerns. Together, these shortcomings leave a substantial unmet need for new, mechanism-specific therapies that can achieve durable remission with fewer side effects.
ABSTRACT Recently, T peripheral helper (Tph) cells, a specific population of B-cell-helping T cells marked by high output of the chemokine CXCL13, have been identified as a key driver of autoantibody production in lupus and RA. This therapeutic platform developed by Northwestern researchers aims to shut down these autoimmune T cells by regulating their internal control switches rather than broadly shutting down the immune system. It identifies the aryl hydrocarbon receptor (AHR) and defined transcription factors as key regulators of a T-cell program that promotes B‑cell activation via a chemokine called CXCL13, which is linked to disease activity and antibody production in lupus and rheumatoid arthritis. The inventors show that activating AHR can reduce the formation and function of these CXCL13‑producing T cells and support an alternative T‑cell state associated with more balanced immune activity. The technology provides compositions and methods that use AHR agonists alone, combined with regulatory transcription factors (AHR, JUN, FOS, ATF3, FOSL1, FOSL2), or paired with CRISPR-based gene editing, to reduce the differentiation and activity of CXCL13-producing Tph and Tfh cells that drive autoantibody-mediated autoimmune disease. Gene-editing, cell-culture, genomic, and patient-sample studies indicate that AHR activity restrains the harmful lupus-associated program, while interferon signaling pushes cells in the opposite direction. In patient-linked analyses, blocking type I interferon signaling reduced a lupus-associated blood signal and shifted T-cell populations away from the disease-driving state, further supporting the pathway’s clinical relevance. This technology represents a potential first-in-class or best-in-class targeted strategy based on AHR activation or related pathway modulation to decrease pathological T cell populations in autoimmune conditions with a clearer mechanistic rationale than broad immune suppression. APPLICATIONS
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