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Published on: May 2, 2025
Depletion of PD-1-positive cells ameliorates autoimmune disease
Peng Zhao1, Peng Wang1, Shuyun Dong1
1Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
Abstract:
Targeted suppression of autoimmune diseases without collateral suppression of normal immunity remains an elusive yet clinically important goal. Targeted blockade of programmed-cell-death-protein-1 (PD-1)-an immune checkpoint factor expressed by activated T cells and B cells-is an efficacious therapy for potentiating immune activation against tumours. Here we show that an immunotoxin consisting of an anti-PD-1 single-chain variable fragment, an albumin-binding domain and Pseudomonas exotoxin targeting PD-1-expressing cells, selectively recognizes and induces the killing of the cells. Administration of the immunotoxin to mouse models of autoimmune diabetes delays disease onset, and its administration in mice paralysed by experimental autoimmune encephalomyelitis ameliorates symptoms. In all mouse models, the immunotoxin reduced the numbers of PD-1-expressing cells, of total T cells and of cells of an autoreactive T-cell clone found in inflamed organs, while maintaining active adaptive immunity, as evidenced by full-strength immune responses to vaccinations. The targeted depletion of PD-1-expressing cells contingent to the preservation of adaptive immunity might be effective in the treatment of a wide range of autoimmune diseases.
Insights
A novel immunotoxin targets programmed-cell-death-protein-1 (PD-1) to selectively eliminate autoimmune cells. This approach effectively treats autoimmune diseases in mice while preserving normal immune function and response to vaccination.
Area of Science:
- Immunology
- Autoimmunity
- Cancer Immunotherapy
Background:
- Targeted suppression of autoimmune diseases without compromising normal immunity is a significant clinical challenge.
- Programmed-cell-death-protein-1 (PD-1) is an immune checkpoint factor on T and B cells, targeted in cancer immunotherapy.
Purpose of the Study:
- To develop and evaluate a novel immunotoxin for targeted suppression of autoimmune diseases.
- To assess the efficacy and safety of PD-1 targeted therapy in preclinical autoimmune models.
Main Methods:
- Construction of an immunotoxin comprising an anti-PD-1 single-chain variable fragment, albumin-binding domain, and Pseudomonas exotoxin.
- Administration of the immunotoxin to mouse models of autoimmune diabetes and experimental autoimmune encephalomyelitis.
Main Results:
- The immunotoxin selectively recognized and induced killing of PD-1-expressing cells.
- Disease onset was delayed in autoimmune diabetes models and symptoms ameliorated in experimental autoimmune encephalomyelitis models.
- Reduced numbers of PD-1-expressing cells, total T cells, and autoreactive T cells in inflamed organs were observed, with preserved adaptive immunity.
Conclusions:
- Targeted depletion of PD-1-expressing cells using this immunotoxin is a promising strategy for treating autoimmune diseases.
- This approach preserves adaptive immunity, suggesting broad applicability for various autoimmune conditions.
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