title: Immunosuppression with 4SC-101, a novel inhibitor of dihydroorotate dehydrogenase, in a rat model of renal transplantation.
abstract: BACKGROUND
  4SC-101 is a novel dihydroorotate dehydrogenase inhibitor and a blocker of interleukin (IL)-17 secretion with beneficial effects in experimental lupus and inflammatory bowel disease. Its immunomodulatory effect on acute kidney rejection is not known; therefore, in this study, the impact of 4SC-101 was examined in a rat model of acute kidney rejection.
  
  
  METHODS
  The kidneys of Brown-Norway rats were orthotopically transplanted into bilaterally nephrectomized Lewis recipients. Allograft recipients were administered with 4SC-101 at dosages of 4, 20, or 60 mg/kg per day, and survival was assessed. In the second setting, the animals were harvested 3 or 5 days after transplantation (Tx), and graft histologic diagnosis was determined. The effects of 4SC-101 on impaired renal function were examined in a model of 5/6 nephrectomy in Lewis rats.
  
  
  RESULTS
  The recipients treated with 20-mg/kg 4SC-101 showed prolonged survival compared with placebo-treated animals (mean±SEM, 24±9.3 vs. 5.4±3 days), paralleled by less severe histologic features of acute kidney rejection such as interstitial/perivascular infiltration and tubulitis 3 and 5 days after Tx, and a lower level of IL-17 messenger RNA 5 days after Tx compared with the placebo-treated animals. In the 5/6 nephrectomy model, 20-mg/kg 4SC-101 reduced proteinuria, glomerulosclerosis, and fibrosis with decreased IL-17 messenger RNA expression.
  
  
  CONCLUSIONS
  4SC-101 prolongs survival after Tx, paralleled by amelioration of histologic signs of acute rejection. Furthermore, it showed no worsening effects on kidney function in a remnant kidney model and even slowed the progression of proteinuria and kidney fibrosis. Therefore, 4SC-101 might be a promising pharmaceutical agent in Tx medicine for further investigations.
authors.affiliation: Department of Nephrology, Klinikum rechts der Isar, Munich, Germany.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Rusai
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmaderer
authors.forename: Marcus
authors.initials: M
authors.lastname: Baumann
authors.forename: Stefan
authors.initials: S
authors.lastname: Chmielewski
authors.forename: Agnes
authors.initials: A
authors.lastname: Prókai
authors.forename: Eva
authors.initials: E
authors.lastname: Kis
authors.forename: Attila J
authors.initials: AJ
authors.lastname: Szabó
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.forename: Robert
authors.initials: R
authors.lastname: Doblhofer
authors.forename: Aldo
authors.initials: A
authors.lastname: Ammendola
authors.forename: Jens
authors.initials: J
authors.lastname: Lutz
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D003998:Dicarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000090722:Dihydroorotate Dehydrogenase; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005355:Fibrosis; D006084:Graft Rejection / Q000401:mortality / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020381:Interleukin-17 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology* / Q000401:mortality; D008297:Male; D009392:Nephrectomy; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors; D011183:Postoperative Complications / Q000517:prevention & control; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001713:Biphenyl Compounds; D003998:Dicarboxylic Acids; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D020381:Interleukin-17; C553728:vidofludimus; D044925:Oxidoreductases Acting on CH-CH Group Donors