title: Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial.
abstract: BACKGROUND
  There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy.
  
  
  METHODS
  In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months.
  
  
  RESULTS
  TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6-98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up.
  
  
  CONCLUSIONS
  In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full-scale study will be needed to confirm our findings.
  
  
  BACKGROUND
  EudraCT Number: 2006-003110-18.
authors.affiliation: Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.|Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Viklicky
authors.affiliation: Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Hruba
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tomiuk
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schmitz
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gerstmayer
authors.affiliation: Institute of Medical Immunology, Charité University Medicine Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Medicine (BCRT), Charité University Medicine Berlin, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.affiliation: Institut National de la Santé et de la Recherche Médicale INSERM U1064, France.|Institut de Transplantation Urologie Néphrologie du Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Miqueu
authors.affiliation: Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Mrazova
authors.affiliation: Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Irena
authors.initials: I
authors.lastname: Tycova
authors.affiliation: Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Svobodova
authors.affiliation: Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Honsova
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Janssen
authors.affiliation: Institute of Medical Immunology, Charité University Medicine Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Medicine (BCRT), Charité University Medicine Berlin, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.affiliation: Berlin-Brandenburg Center for Regenerative Medicine (BCRT), Charité University Medicine Berlin, Germany.|Department of Nephrology and Intensive Care Medicine, Charité University Medicine Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
mesh_terms: D000328:Adult; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015415:Biomarkers / Q000378:metabolism; D000074301:CD52 Antigen; D005260:Female; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic; D011446:Prospective Studies; D020123:Sirolimus / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015415:Biomarkers; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D020123:Sirolimus; D016559:Tacrolimus