Linsitinib, an IGF-1R inhibitor, prevents immune activation of the bone marrow in experimental Graves’ disease and thyroid eye disease:
Author: Anne Gulbins
Base Hospital / Institution: Department of Ophthalmology, Essen, Germany
Rapid fire oral presentation
Abstract ID: 24-178
Purpose
Graves’ disease is an autoimmune disease caused by autoantibodies to the TSHR. Overstimulation of the TSHR induces hyperthyroidism and thyroid eye disease (TED), the most common extra-thyroidal manifestation of GD. In TED, the TSHR cross-talks with the IGF-1R in orbital fibroblasts. The bone marrow plays an important role in autoimmune diseases, however its role in GD and TED is largely unknown. Here, we investigated whether the induction of experimental GD and TED involves activation of the bone marrow and whether interference with IGF-1R signaling by linsitinib, a small molecule inhibitor of the IGF-1R, prevents this activation process.
Methods
Mice were immunized three times with a plasmid encoding for the A-subunit of the TSHR to induce GD and associated TED. Linsitinib was given for four weeks and the experiment was terminated six weeks after the last immunization.
Results
Immunization of mice with the TSHR resulted in an increase in T-cells, indicating their infiltration, and a decrease in myeloid cells, indicating their mobilization from the bone marrow. Both was prevented by linsitinib. In addition, we observed an increase in Sca1+ hematopoietic stem cells after TSHR immunization, demonstrating bone marrow activation. Immunization also resulted in an upregulation of proinflammatory cytokines and decrease in anti-inflammatory cytokines in the bone marrow which was blocked by linsitinib. We also demonstrate a downregulation of arginase-1 expression in the bone marrow of TSHR-immunized mice, with a concomitant increase in local arginine. Linsitinib induces upregulation of arginase-1, resulting in low bone marrow arginase levels, and therefore an immunosuppressive microenvironment.
Conclusion
In summary, we propose that the bone marrow is as a novel key player in the pathogenesis of TED, triggering the autoinflammatory response and promoting the disease. Linsitinib blocks bone marrow activation, thereby inhibiting onset and progression of TED. Our findings provide insights into a new understanding of the disease and new therapeutic options, highlighting the clinical significance of our findings.
Additional Authors
| First name | Last name | Base Hospital / Institution |
|---|---|---|
| Mareike | Horstmann | Department of Ophthalmology, Essen, Germany |
| Simone | Keitsch | Department of Molecular Biology, Essen, Germany |
| Matthias | Soddemann | Department of Molecular Biology, Essen, Germany |
| Barbara | Wilker | Department of Molecular Biology, Essen, Germany |
| Gregory C. | Wilson | Department of Surgery, Cincinnati, Ohio, USA |
| Ryan | Zeidan | Sling Therapeutics Inc., Ann Arbor, MI, USA |
| Gary D. | Hammer | University of Michigan, Ann Arbor, MI, USA |
| Anke | Daser | Department of Oto-Rhino- Laryngology |
| Nikolaos E. | Bechrakis | Department of Ophthalmology, Essen, Germany |
| Gina-Eva | Goertz | Department of Ophthalmology, Essen, Germany |
| Anja | Eckstein | Department of Ophthalmology, Essen, Germany |
