title: NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging.
abstract: To explore phenotype and function of NK cells in kidney transplant recipients, we investigated the peripheral NK cell repertoire, capacity to respond to various stimuli and impact of immunosuppressive drugs on NK cell activity in kidney transplant recipients. CD56dim NK cells of kidney transplanted patients displayed an activated phenotype characterized by significantly decreased surface expression of CD16 (p=0.0003), CD226 (p<0.0001), CD161 (p=0.0139) and simultaneously increased expression of activation markers like HLA-DR (p=0.0011) and CD25 (p=0.0015). Upon in vitro stimulation via Ca++-dependent signals, down-modulation of CD16 was associated with induction of interferon (IFN)-γ expression. CD16 modulation and secretion of NFAT-dependent cytokines such as IFN-γ, TNF-α, IL-10 and IL-31 were significantly suppressed by treatment of isolated NK cells with calcineurin inhibitors but not with mTOR inhibitors. In kidney transplant recipients, IFN-γ production was retained in response to HLA class I-negative target cells and to non-specific stimuli, respectively. However, secretion of other cytokines like IL-13, IL-17, IL-22 and IL-31 was significantly reduced compared to healthy donors. In contrast to suppression of cytokine expression at the transcriptional level, cytotoxin release, i.e. perforin, granzyme A/B, was not affected by immunosuppression in vitro and in vivo in patients as well as in healthy donors. Thus, immunosuppressive treatment affects NK cell function at the level of NFAT-dependent gene expression whereby calcineurin inhibitors primarily impair cytokine secretion while mTOR inhibitors have only marginal effects. Taken together, NK cells may serve as indicators for immunosuppression and may facilitate a personalized adjustment of immunosuppressive medication in kidney transplant recipients.
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School Hannover, Hannover, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School Hannover, Hannover, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Neudörfl
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School Hannover, Hannover, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Daemen
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School Hannover, Hannover, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Keil
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School Hannover, Hannover, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Stevanovic-Meyer
authors.affiliation: Department of Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lehner
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany; Institute of Technical Chemistry, Leibniz University Hannover, Hannover, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Blume
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School Hannover, Hannover, Germany; DZIF, German Center for Infectious Diseases, Hannover / Braunschweig, Germany.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D020013:Calcium Signaling / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D023001:Transplantation Tolerance / Q000187:drug effects*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D007166:Immunosuppressive Agents