Aivars Kalnins1, Michael Thomas1, M. Andrassy2, Sebastian Müller3, Alexandra Wagner1, Sebastian Pratschke1, Markus Rentsch1, JP Klußmann4, Teresa Kauke1, Martin K. Angele1, Alexandr V. Bazhin1, Michael Fischereder5, Jens Werner1, Markus Guba1, Joachim Andrassy1
1Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany
2Department of Medicine, Rupprecht-Karl's University, Heidelberg, Germany
3Department of Pathology, Ludwig-Maximilian's University, Munich, Germany
4NOXXON Pharma AG, Berlin, Germany
5Division of Nephrology, Department of Medicine, Med IV, Ludwig-Maximilian's University, Munich, Germany
Tóm tắt
AbstractThe rejection process remains the key unsolved issue after transplantation of disparate tissue. The CC chemokine monocyte chemoattractant protein‐1 (MCP‐1/CCL2) has been reported to be involved in the process of alloimmune interaction. Spiegelmers are l‐oligonucleotides that can be designed to bind to pharmacologically relevant target molecules. Here, we tested a high‐affinity Spiegelmer‐based MCP‐1 inhibitor (mNOX‐E36) in an allogeneic heart transplant model. Fully vascularized allogeneic heterotopic heart transplantations from BALB/c to C57BL/6 mice were performed. Mice were either treated with the anti‐MCP‐1‐Spiegelmer (mNOX‐E36) in monotherapy or in combination with subtherapeutic doses of cyclosporine A (CsA) (10 mg/kgBW/day) for 10 days. Controls received equivalent doses of a non‐functional Spiegelmer (revmNOX‐E36). Graft survival of allogeneic heart transplants was slightly but significantly prolonged under mNOX‐E36 monotherapy (median graft survival 10 day ± 0.7) compared to revmNOX‐E36 (median graft survival 7 day ± 0.3; P = 0.001). A synergistic beneficial effect could be seen when mNOX‐E36 was administered in combination with subtherapeutic doses of CsA (18 day ± 2.8 versus 7 day ± 0.3; P < 0.0001). Levels of inflammatory cytokines and ‘alarmins’ were significantly reduced, and the number of F4/80+ cells was lower under combination therapy (1.8% ± 1.3%; versus 14.6% ± 4.4%; P = 0.0002). This novel inhibitor of the MCP‐1/CCR2 axis (mNOX‐E36), which has already proven efficacy and tolerability in early clinical trials, alleviates acute rejection processes in allogeneic transplantation especially when combined with subtherapeutic doses of CsA. Thus, mNOX‐E36 may have potential as an adjunct immunomodulatory agent.
