title: Graft dysfunction in chronic antibody-mediated rejection correlates with B-cell-dependent indirect antidonor alloresponses and autocrine regulation of interferon-γ production by Th1 cells.
abstract: Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody-mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-γ production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4+T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell-driven interferon-γ production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4+T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-γ production.
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Kin Yee
authors.initials: KY
authors.lastname: Shiu
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: McLaughlin
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Rebollo-Mesa
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Jingyue
authors.initials: J
authors.lastname: Zhao
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Burton
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Harriet
authors.initials: H
authors.lastname: Douthwaite
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Wilkinson
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Vikki
authors.initials: V
authors.lastname: Semik
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Dodd
authors.affiliation: Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Brookes
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lechler
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Hernandez-Fuentes
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kemper
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK. Electronic address: anthony.dorling@kcl.ac.uk.
authors.forename: Anthony
authors.initials: A
authors.lastname: Dorling
mesh_terms: D000328:Adult; D019540:Area Under Curve; D019898:Autocrine Communication / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D001706:Biopsy; D016009:Chi-Square Distribution; D002908:Chronic Disease; D018450:Disease Progression; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D006085:Graft Survival; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D059425:Interferon-gamma Release Tests; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D007518:Isoantibodies / Q000097:blood*; D007668:Kidney / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D012372:ROC Curve; D012307:Risk Factors; D015398:Signal Transduction; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D006680:HLA Antigens; C573415:IFNG protein, human; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: B lymphocyte; ELISPOT; chronic allograft nephropathy; indirect alloresponses; interferon-γ