Clinical development of tacrolimus-resistant regulatory T cells to enable simultaneous immunosuppression and immune regulation.

Authors

Ghazaleh Zarrinrad, Lisa-Marie Burkhardt, Claudia Beltran-Mestres, Silvina Romero-Suárez, Dimitrios Laurin Wagner, Stephan Schlickeiser, Maik Stein, Désirée Jacqueline Wendering, Iván Juky Carrera Diaz de la Cebosa, Lukas Ehlen, Frederik Hamm, Gavin L Kurgan, Pawel Durek, Frederik Heinrich, Anamika Giri, Yaolin Pu, Kristy Ou, Henrike Hoffmann, Sandra Muench, Insa Stuewe, Sven Dolling, Oliver McCallion, Jaspal Kaeda, Jonas Kath, Sarah Schulenberg, Niklas Wiese, Abdolreza Nazari, Lena Peter, Samira Picht, Andrea Sánchez-Peña, Olalekan Usman, Christian Brommel, Rolf Turk, Garrett Rettig, Morgan Sturgeon, Thomas L Osborne, Ashley Jacobi, Rebecca Friedrich, Masako Monika Kaufmann, Julia Klermund, Simon Fink, Markus F Templin, Andy Roemhild, Daniel Kaiser, Oliver Klein, Toni Cathomen, Mir-Farzin Mashreghi, Fadi Issa, Julia K Polánsky, Hans-Dieter Volk, Michael Schmueck-Henneresse, Petra Reinke, Leila Amini

Published in

Molecular therapy. Advances. Volume 34. Issue 2. Pages 201735. Jun 11, 2026. Epub Apr 09, 2026.

Abstract

Unwanted alloimmune responses are a central driver of solid organ transplant rejection and currently managed with life-long immunosuppression, which imposes substantial risks and burdens on patients. Adoptive transfer of regulatory T cells (Tregs) offers a strategy to restore immunological balance and reduce long-term adverse effects of generalized immunosuppression. However, although Tregs can potently inhibit incipient immune activation, they struggle to suppress established memory effector T cells, necessitating the continued use of immunosuppression. Calcineurin inhibitors such as Tacrolimus effectively control both, newly activated and pre-existing effector T cells, but unfortunately, they also impair Treg function. Therefore, we hypothesized that gene-editing of Tregs inducing tacrolimus resistance (FKBP12^KO) would enable combined therapy that curbs effector T cell responses without compromising Treg efficacy. Here, we developed FKBP12^KO-Tregs using a ribonucleoprotein-based CRISPR-Cas9 approach and characterized them extensively in vitro. FKBP12^KO-Tregs retained phenotype, high viability, and suppressive function comparable to unedited Treg^WT, and they remained functionally impervious to Tacrolimus, while preserving sensitivity to alternative CNIs. We additionally established a good-manufacturing practice process for FKBP12^KO-Tregs. Comprehensive in vitro phenotypic, functional, and molecular characterization, together with the established manufacturing, provide the rationale for a proof-of-concept clinical trial assessing the feasibility and safety of co-administration of FKBP12^KO-Tregs with Tacrolimus in living-donor kidney transplant recipients.

PMID:
42147444
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.