title: Spiegelmer Inhibition of MCP-1/CCR2--Potential as an Adjunct Immunosuppressive Therapy in Transplantation.
abstract: The 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.
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kalnins
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: M N
authors.initials: MN
authors.lastname: Thomas
authors.affiliation: Department of Medicine, Rupprecht-Karl's University, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Andrassy
authors.affiliation: Department of Pathology, Ludwig-Maximilian's University, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Pratschke
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rentsch
authors.affiliation: NOXXON Pharma AG, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Klussmann
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Kauke
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: M K
authors.initials: MK
authors.lastname: Angele
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: A V
authors.initials: AV
authors.lastname: Bazhin
authors.affiliation: Division of Nephrology, Department of Medicine, Med IV, Ludwig-Maximilian's University, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Fischereder
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Werner
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Guba
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilian's-University Munich, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Andrassy
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous
chemical_list: D052157:Aptamers, Nucleotide; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; C541611:NOX-E36 aptamer; D054390:Receptors, CCR2; D016572:Cyclosporine