title: B-cell-related biomarkers of tolerance are up-regulated in rejection-free kidney transplant recipients.
abstract: BACKGROUND
  Molecular signatures have recently been identified in operationally tolerant long-term kidney transplant patients; however, their expression in patients on immunosuppression remains unclear.
  
  
  METHODS
  In this prospective study, the gene expression profiles of eight selected tolerance-associated genes (MS4A1, CD79B, TCL1A, TMEM176B, FOXP3, TOAG-1, MAN1A1, and TLR5) in the peripheral blood of 67 kidney transplant recipients at days 0, 7, 14, 21, 28, 60, 90, and at 6 and 12 months, and in graft biopsies were measured. Similarly, using flow cytometry, CD45CD19CD3 B-cell counts were evaluated in the follow-up. Expression patterns were compared among patients with biopsy-proven acute rejection, borderline changes, and in rejection-free patients. A generalized linear mixed model with gamma distribution for repeated measures adjusted for induction therapy was used for statistical analysis of longitudinal data and Kruskal-Wallis test for case biopsy data.
  
  
  RESULTS
  Compared to patients with rejection, a significantly higher number of peripheral B cells were observed during follow-up in rejection-free patients and in patients with borderline changes. Gene expression patterns of MS4A1 (CD20), TCL1A, CD79B, TOAG-1, and FOXP3 genes were significantly higher in rejection-free patients as compared to rejection group with the highest differences during the first 3 months. In contrast, TMEM176B (TORID) was up-regulated in the rejection group. Similar trends were also observed between patients with borderline changes and acute rejection. Higher intragraft expression of TOAG-1 was observed in rejection-free patients.
  
  
  CONCLUSIONS
  These observations suggest an association of B-cell signatures, seen also in drug-free tolerant patients, with controlled alloimmune response.
authors.affiliation: Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. ondrej.viklicky@medicon.cz
authors.forename: Ondrej
authors.initials: O
authors.lastname: Viklicky
authors.forename: Eva
authors.initials: E
authors.lastname: Krystufkova
authors.forename: Irena
authors.initials: I
authors.lastname: Brabcova
authors.forename: Alena
authors.initials: A
authors.lastname: Sekerkova
authors.forename: Peter
authors.initials: P
authors.lastname: Wohlfahrt
authors.forename: Petra
authors.initials: P
authors.lastname: Hribova
authors.forename: Mariana
authors.initials: M
authors.lastname: Wohlfahrtova
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.forename: Janka
authors.initials: J
authors.lastname: Slatinska
authors.forename: Ilja
authors.initials: I
authors.lastname: Striz
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology*; D015415:Biomarkers; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D020869:Gene Expression Profiling; D006084:Graft Rejection; D006801:Humans; D007108:Immune Tolerance; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human