Biology subjects

Ehlen, L.

Publications and source records attributed to Ehlen, L..

2 recordsLinked to original sources

bioRxiv2025

Clinical development of gene edited tacrolimus-resistant Treg (FKBP12KO-Treg) to enable simultaneous immunosuppression and support of immune regulation

Background: Unwanted immune responses play a central role in the pathogenesis of solid organ allograft rejection. These are managed by life-long immunosuppression with considerable burden for the patient and society. Adoptive therapy with regulatory T-cells (Treg) is a promising approach to restore sustainable immune balance and avoid long-term adverse effects of immunosuppression. While Treg effectively inhibit activation of unwanted immune responses, they are less effective in controlling pre-existing/activated memory effector T-cells (Teff). Thus, co-administration of Treg with immunosuppressants is required to achieve a sustainable organ acceptance. Calcineurin inhibitors (CNI) are powerful in controlling de novo generated and preformed Teff. However, CNI also dampen Treg immunoregulatory function. Thus, we hypothesize improved results of adoptive Treg therapy in immunosuppressed patients applying tacrolimus-resistant Treg. Methods: While retaining CNI modulation of Teff with tacrolimus, we knocked-out FKBP12 in Treg (FKBP12KO-Treg) by gene-editing using ribonucleoprotein-based CRISPR/Cas9 technology to generate tacrolimus-resistant Treg and characterised them using flow cytometry, functional assays and in-depth phenotyping. Results: This detailed in vitro analysis showed FKBP12KO-Treg were comparable to non-gene edited Treg and impervious to tacrolimus while maintaining immunoregulatory function and sensitivity to alternative CNIs raising no safety concerns. Furthermore, we aligned our methodology to achieve GMP compliance laying the basis for a manufacturing license in preparation of a clinical trial. Conclusion: Based on the presented preclinical dataset implying safety and efficacy of FKBP12KO-Treg, we are now seeking to undertake a proof-of-concept clinical trial to evaluate the co-administrationof FKBP12KO-Treg and tacrolimus to enhance the management of living donor kidney transplant recipients.

immunology↗

bioRxiv2025

Sympathetic signaling directs macrophage efferocytosis in thermogenic adipose tissue

Brown adipose tissue (BAT) undergoes significant remodeling upon thermogenic activation. During this process, brown adipocytes and immune cells, such as macrophages, contribute to thermogenesis and energy expenditure. Among the various functions exerted by macrophages, the clearance of dying cells, known as efferocytosis, is a key regulator of tissue remodeling across multiple organs in both physiological and pathological contexts. However, whether macrophages contribute to BAT remodeling and thermogenic adaptation through efferocytosis, and what drives efferocytosis in BAT, remain unknown. Here, we identify norepinephrine (NE), which is highly released in BAT upon cold challenge, as a tissue-specific trigger of macrophage efferocytosis. Transcriptomic and lipidomic analyses of BAT after cold exposure revealed a population of lipid-handling macrophages enriched in efferocytosis-related transcripts. Consistently, cold exposure enhanced the efferocytic capacity of BAT macrophages. These effects were recapitulated by stimulation of macrophages with NE and were dependent on {beta}2-adrenergic signaling and the efferocytic receptors AXL and MERTK. Mice lacking Axl and Mertk in macrophages exhibited impaired lipolysis, reduced thermogenic gene expression, and increased adipose tissue inflammation. Together, our findings identify a so far neglected role for NE in adipose tissue, linking sympathetic activation to macrophage efferocytosis and thereby promoting tissue remodeling and metabolic adaptation. Uncovering the role of NE in one of the core functions of macrophages, efferocytosis, not only expands our understanding of the multifaceted effects of NE on the immune system but also highlights therapeutic potential for targeting impaired efferocytosis in metabolic disorders. One sentence summaryNorepinephrine is a novel trigger of macrophage efferocytosis in brown adipose tissue, linking sympathetic signaling to metabolic adaptation and macrophage tissue remodeling responses through {beta}2-adrenergic and Axl/Mertk pathways.

immunology↗