title: Substantial proliferation of human renal tubular epithelial cell-reactive CD4+CD28null memory T cells, which is resistant to tacrolimus and everolimus.
abstract: BACKGROUND
  In spite of maintenance treatment with immunosuppressive drugs, tubulitis still occurs and can lead to structural kidney graft damage. We hypothesize that human renal tubular epithelial cells (TECs) trigger selective proliferation of recipient T-cell subsets with variable sensitivity to immunosuppressive drugs.
  
  
  METHODS
  Recipient peripheral blood mononuclear cells were cocultured with donor-derived TECs for 7 days. The proliferation of the total CD4 T-cell pool was assessed. Next, we analyzed which CD4 T-cell subset proliferated and how this response was affected by tacrolimus, everolimus, prednisolone, and mycophenolic acid (MPA) in clinically relevant concentrations.
  
  
  RESULTS
  CD4 T-cell proliferation upon TEC encounter was mainly executed by memory T cells. Interestingly, 38%±7% of the proliferating CD4 T-cell pool showed a CD28 phenotype. These proliferating CD4CD28 memory T cells produced high levels of interferon-γ, tumor necrosis factor-α, and the cytolitic protease granzyme B. TEC-reactive CD4 T-cell proliferation was significantly suppressed by tacrolimus, everolimus, prednisolone, and MPA (P<0.05). Surprisingly and in contrast to prednisolone and MPA, neither tacrolimus nor everolimus could inhibit the CD4CD28 T-cell proliferative response.
  
  
  CONCLUSIONS
  Our data show substantial proliferation of TEC-reactive CD4CD28 memory T cells, which are resistant to tacrolimus and everolimus. This phenomenon might play an important mechanistic role during cellular rejection under full immunosuppression.
authors.affiliation: 1 Department of Internal Medicine, Division of Nephrology and Kidney Transplantation, Erasmus MC-University Medical Center Rotterdam, The Netherlands. 2 Department of Surgery, Division of Transplant Surgery, Erasmus MC-University Medical Center Rotterdam, The Netherlands. 3 Address correspondence to: Martijn W.H.J. Demmers, M.Sc., Department of Internal Medicine, Division of Nephrology and Kidney Transplantation, Erasmus MC-University Medical Center Rotterdam, Ee563a, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands and Ajda T. Rowshani, M.D., Ph.D., Department of Internal Medicine, Division of Nephrology and Kidney Transplantation, Erasmus MC-University Medical Center Rotterdam, D-412, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Martijn W H J
authors.initials: MW
authors.lastname: Demmers
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.forename: Malou
authors.initials: M
authors.lastname: Janssen
authors.forename: Nicolle H R
authors.initials: NH
authors.lastname: Litjens
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Michiel G
authors.initials: MG
authors.lastname: Betjes
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Ajda T
authors.initials: AT
authors.lastname: Rowshani
mesh_terms: D000328:Adult; D018106:CD28 Antigens / Q000172:deficiency* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004351:Drug Resistance; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects; D007684:Kidney Tubules / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000494:pharmacology; D010641:Phenotype; D011239:Prednisolone / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; C573415:IFNG protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000068338:Everolimus; D011239:Prednisolone; C509213:GZMB protein, human; D053804:Granzymes; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus