Potential of small molecule Bcl-6 inhibitors as novel immunosuppressive agents in organ transplantation

• Applicant: Dr. Louisa Steines
• Subject Area: Nephrology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539135458

Antibody-mediated rejection (ABMR) has been identified as a major cause of graft failure in kidney transplantation (Ktx). Current immunosuppressive treatments insufficiently inhibit the formation of donor-specific antibodies (DSA) and have unfavourable side-effects. Furthermore, although B cells are the precursors of antibody-secreting cells, B cells are not specifically targeted by standard immunosuppression in Ktx recipients. To improve outcomes in Ktx, immunosuppressive therapies effectively targeting humoral immunity need to be developed. The activation, selection and proliferation of allo-specific B cells takes place in the B cell follicles of secondary lymphoid organs. Here, B cells are activated by specialized T follicular helper cells (Tfh). The transcription factor Bcl-6 is required for the development of Tfh and for the differentiation of activated B cells in the context of the germinal center (GC) reaction, from which allo-specific plasma cells and memory B cells arise. Bcl-6 is therefore essential for the generation of the humoral alloimmune response and the development of high affinity pathogenic DSA. The inhibition of Bcl-6 may thus block the development of allo-specific plasma cells and memory B cells, as well as DSA, and present a novel mechanism to prevent ABMR in Ktx. Using Bcl-6 inhibitors as immunosuppressive agents in Ktx is a novel concept. In this project, we aim to assess 1.) the role of Bcl-6 in immunological risk in Ktx and waitlist patients, 2.) to test the effect of Bcl-6 inhibitors in a translational Ktx model in rats, and 3.) to explore the mechanism of Bcl-6 inhibitors in human Tfh and B cells. We hereby plan to demonstrate the principle of Bcl-6 inhibition as a novel mechanism of immunosuppression in Ktx.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Co-Investigators: Professorin Dr. Kerstin Amann; Dr. Henrik Junger
• Cooperation Partner: Professorin Dr. Carla Baan