Thorac Cardiovasc Surg 2015; 63 - OP163
DOI: 10.1055/s-0035-1544415

Proteasome Inhibitors in Experimental Cardiac Transplantation

M. Waechter 1, 2, B. Reichart 1, J. Kindermann 1, 2, T. Mayr 1, 2, P. Brenner 1, 2, C. Hagl 2, M. Langenmayer 3, R. Wanke 3, P. Beck 4, M. Groll 4, J. Abicht 1, 5, S. Guethoff 1, 2
  • 1Transregio Collaborative Research Center 127, Ludwig-Maximilians University Munich, München, Germany
  • 2Department of Cardiac Surgery, Ludwig-Maximilian University Munich, München, Germany
  • 3Institute of Veterinary Pathology, Ludwig-Maximilians University Munich, München, Germany
  • 4Munich Center for Integrated Protein Science at the Department of Chemistry, Technical University Munich, Garching, Germany
  • 5Department of Anaesthesiology, Ludwig-Maximilians University Munich, München, Germany

Objectives: Proteasome inhibition by bortezomib, a constitutive proteasome inhibitor (PI) approved for the treatment of multiple myeloma, was reported in the field of organ transplantation; despite known role in antigen presentation, the positive effect on graft rejection has not been verified. Since bortezomib is associated with many side effects (pancytopenia, gastrointestinal and transient neurological disorders), specific inhibition of immunoproteasomes might reduce them. The currently unapproved immunospecific PI PR-957 achieved positive results in experimental mice studies in the field of autoimmune diseases. Therefore, we compared the treatment with PR-957 and Bortezomib in a rat model of heterotopic heart transplantation.

Methods: Brown Norway rat cardiac allografts were heterotopic abdominal transplanted to Lewis rats using microvascular Langendorff technique. Since postoperative day (POD) 1 recipients were daily treated intravenously with bortezomib (0.1 mg/kg), PR-957 (6 mg/kg) or saline (control, n = 6 in each group). The primary end point of the study was graft survival, determined by daily graft palpation and echocardiography. All explanted hearts were collected for histological analyses. A tolerance study was performed treating Lewis rats daily with bortezomib, PR-957 or saline for 16 days (n = 3 in each group). Blood counts of all treated rats were determined every other day.

Results: Mean graft survival was 6.8 ± 0.8d in control group versus 11.5 ± 2.9d (p = 0.002 vs control) in bortezomib, and 11.2 ± 1.3d (p = 0.002 vs control) in PR-957 group. On POD 7 only recipients treated with bortezomib suffered from thrombocytopenia (p = 0.019). No significant differences in red and white blood counts were detected between the treatment groups. The tolerance study showed macroscopic alterations of liver, lymphnodes and thymus in bortezomib treated animals, whereas autopsy of PR-957 or saline treated animals revealed no macroscopic abnormalities. Histological analyses and measurement of cytokines are ongoing.

Conclusions: Proteasome inhibitors obviously improved allograft survival. Compared with the constitutive PI bortezomib, the treatment with the immunospecific PI PR-957 suggested being superior in avoidance of side effects. Thus, drug development in the new field of immunoproteasome inhibition could improve the treatment of transplant rejection.