Abstract: SA-OR054
Spatially Controlled Immunosuppression with SynNotch T Cells for the Treatment of Kidney Autoimmunity
Session Information
- Glomerular Targeted Therapies: The New Era
November 08, 2025 | Location: Room 310A, Convention Center
Abstract Time: 05:50 PM - 06:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Eckey, Tobias, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Nies, Jasper Friedrich, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Trinsch, Bastian, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Diefenhardt, Paul, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Puetz, David L., Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Sierra Gonzalez, Claudio, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Schermer, Bernhard, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Benzing, Thomas, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Brinkkoetter, Paul T., Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
- Braehler, Sebastian, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany
Background
Crescentic glomerulonephritis (cGN) is a severe T cell–mediated autoimmune disease with limited therapeutic options. Current standard treatments rely on broad systemic immunosuppression, which is frequently associated with significant side effects. Spatially targeted immunomodulation using synthetic suppressor cells offers a promising strategy to minimize off-target toxicity while preserving therapeutic efficacy.
Methods
We employed retroviral transduction to deliver a synthetic Notch (SynNotch) receptor-based circuit into primary murine T cells, enabling flexible modulation of both input recognition and output response. The circuit is activated upon binding to a predefined target antigen, triggering a downstream synthetic transcriptional program that drives the expression of user-defined effector proteins. Using scRNA-seq, qPCR, and immunofluorescence, we identified the inflammation-associated protein VCAM1 as a suitable target antigen. As circuit outputs, we selected the immunosuppressive molecules IL-10 and PD-L1 to mediate localized immune regulation. SynNotch-engineered T cells were purified by FACS and characterized both in vitro and in vivo to assess their phenotype and functional properties.
Results
VCAM1 is minimally expressed in healthy kidneys but is strongly upregulated in the glomeruli and tubulointerstitium under inflammatory conditions. We validated the functionality of the SynNotch circuit in primary murine T cells by demonstrating IL-10 secretion and PD-L1 surface expression following co-culture with VCAM1-overexpressing HEK293 sender cells. In vivo, SynNotch T cells persisted in Rag1-/- mice and were detectable in the kidneys, spleen, and peripheral blood, confirming their survival and systemic distribution.
Conclusion
We present a novel therapeutic approach for kidney autoimmunity based on immunosuppressive SynNotch T cells. We successfully equipped primary murine T cells with a custom-designed SynNotch circuit, validated its functionality in vitro, and demonstrated the in vivo persistence of the modified T cells. The therapeutic potential of these cells will next be evaluated in the nephrotoxic nephritis (NTN) model, which could have wider implications for the treatment of auto- and alloimmunity.
Funding
- Government Support – Non-U.S.