Selective Immune Silencing by Targeted TGF-β Agonists.

Area of Science:

• Immunology
• Cell Biology
• Drug Discovery

Background:

• Current therapies for immunological diseases deplete T and B cells but have limitations including adverse events and relapse.
• Transforming growth factor beta (TGF-β) possesses immunosuppressive properties that can be harnessed for therapeutic benefit.

Purpose of the Study:

• To develop a novel therapeutic strategy using targeted TGF-β agonists to selectively silence pathogenic T and B cells.
• To evaluate the efficacy and safety of cell-selective TGF-β agonism in preclinical models.

Main Methods:

• Development of helminth-derived TGF-β mimic agonists targeting specific T cell (CD4, CD8) and B cell (CD19) populations.
• Assessment of T cell activation and expansion in mice and human spleen organoids.
• Evaluation of antibody responses and B cell differentiation in human spleen organoids.
• Testing of cell-type-specific TGF-β agonists in mouse models of immunological diseases.

Main Results:

• T cell-targeted TGF-β agonists effectively silenced antigen-stimulated T cell activation and expansion.
• CD4 T cell-targeted agonists reprogrammed T cells to quiescent or regulatory phenotypes, silencing antibody responses.
• CD19 B cell-targeted agonists disrupted B cell differentiation into antibody-secreting cells.
• Cell-selective TGF-β agonists ameliorated disease activity in mouse models with minimal off-target effects.

Conclusions:

• Cell-selective TGF-β agonism represents a versatile therapeutic strategy for precise immune function silencing.
• This approach offers a promising alternative to broad immune cell depletion for treating immunological diseases.