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Clarifying Mechanisms of Treg Function as a Basis for SLE Therapy

Posted December 2, 2022

Charles Fathman, M.D., Stanford University School of Medicine

Charles Fathman, M.D., Stanford University School of Medicine Charles Fathman, M.D.,
(Photo provided)

Dr. Charles Garrison (Garry) Fathman, M.D., Stanford University School of Medicine, received an award from the Congressionally Directed Medical Research Programs’ Lupus Research Program. The award is titled, “Identification, Characterization, and Correction of a Defect in Treg Function in SLE.”

Regulatory T cells (Tregs) maintain self-tolerance, and a loss of Treg function contributes to the development of various autoimmune diseases, including systemic lupus erythematosus (SLE). The Principal Investigator’s laboratory previously identified a druggable defect in the Tregs of patients with SLE. Dr. Fathman’s lab showed that the Tregs of SLE patients express reduced levels of a protein, GRAIL, which is essential to Treg function. In healthy individuals, GRAIL inhibits desensitization of the IL-2 receptor (IL-2R) in Tregs to support transcription of the genes required for Treg function. Reduced GRAIL expression in SLE patients results in a loss of IL-2 activity via diminished inhibition of IL-2R desensitization and ultimately, diminished Treg function and loss of self-tolerance (autoimmunity).

The project extends previous findings of Dr. Fathman’s work by examining the role of Tregs in SLE. His studies will test the hypothesis that most SLE patients have a common defect in their Tregs (GRAIL deficiency) and that the defect in IL-2R signaling and Treg function can be repaired using a human thioredoxin/IL-2 fusion protein drug conjugate to deliver a small molecule drug to restore GRAIL’s function.

The aims of the award are to develop an assay that can identify the subset of SLE patients that have a defect in Treg function and to develop a treatment that can repair the IL-2R signaling defect in their Tregs. This treatment will enhance or restore Treg function and self-tolerance in SLE patients. Successful completion of the award’s aims will represent a paradigm shift in therapy in which autoimmune diseases are treated by the restoration of immune tolerance rather than using immunosuppressive drugs to inhibit inflammatory effector cells.

Links:
Public and Technical Abstracts: Identification, Characterization, and Correction of a Defect in Treg Function in SLE

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Last updated Friday, December 2, 2022