title: B-lymphocytes support and regulate indirect T-cell alloreactivity in individual patients with chronic antibody-mediated rejection.
abstract: We explored how B-lymphocytes influence in vitro T-cell alloresponses in patients with antibody-mediated rejection (AMR), testing whether B-cells would be preferentially involved in this group of patients. Peripheral blood mononuclear cells were collected from 65 patients having biopsy: 14 patients with AMR and 5 with no pathology on protocol; 38 with AMR and 8 with nonimmunologic damage on 'for cause'. Using enzyme-linked immunosorbent spot assays, we found interferon-γ production by indirect allorecognition in 45 of 119 total samples from the 65 patients. B-cells preferentially processed and presented donor alloantigens in samples from AMR patients. In a further 25 samples, B-cell-dependent allo-specific reactivity was shown by depletion of CD25(+) cells and these individuals had higher percentages of CD4CD25hi cells. In 21 samples, reactivity was shown by depletion of CD19(+) cells, associated with polarized cytokine production toward IL-10 after polyclonal activation by IgG/IgM. Overall, this shows a significant contribution by B-cells to indirect donor-specific T-cell reactivity in vitro in patients with AMR. Active suppression by distinct phenotypes of T- or B-cells in approximately half of the patients indicates that chronic AMR is not characterized by a universal loss of immune regulation. Thus, stratified approaches that accommodate the heterogeneity of cell-mediated immunity might be beneficial to treat graft dysfunction.
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Kin Y
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: Vikki
authors.initials: V
authors.lastname: Semik
authors.affiliation: West London Renal and Transplant Centre, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: West London Renal and Transplant Centre, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Candice
authors.initials: C
authors.lastname: Roufosse
authors.affiliation: West London Renal and Transplant Centre, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Brookes
authors.affiliation: West London Renal and Transplant Centre, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Bowers
authors.affiliation: West London Renal and Transplant Centre, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Galliford
authors.affiliation: West London Renal and Transplant Centre, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Taube
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: Anthony
authors.initials: A
authors.lastname: Dorling
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001706:Biopsy; D002450:Cell Communication; D002478:Cells, Cultured; D002908:Chronic Disease; D058501:Enzyme-Linked Immunospot Assay; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D056724:Immunity, Humoral; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D059425:Interferon-gamma Release Tests; D007518:Isoantibodies / Q000276:immunology / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D007668:Kidney / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008213:Lymphocyte Activation; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C573415:IFNG protein, human; D007518:Isoantibodies; D007519:Isoantigens; D007371:Interferon-gamma
references.citation: Nephrology (Carlton). 2009 Feb;14(1):123-32
references.pmid: 19207859
references.citation: Am J Transplant. 2012 May;12(5):1168-79
references.pmid: 22300601
references.citation: Immunity. 2010 Jan 29;32(1):129-40
references.pmid: 20079667
references.citation: Transplantation. 2009 May 27;87(10):1505-13
references.pmid: 19461487
references.citation: Lancet. 2005 Apr 30-May 6;365(9470):1570-6
references.pmid: 15866311
references.citation: J Immunol. 2005 Oct 1;175(7):4180-3
references.pmid: 16177055
references.citation: Am J Transplant. 2009 Nov;9(11):2520-31
references.pmid: 19843030
references.citation: Transplantation. 2006 Feb 15;81(3):398-407
references.pmid: 16477227
references.citation: J Am Soc Nephrol. 2014 Jul;25(7):1575-85
references.pmid: 24610932
references.citation: J Am Soc Nephrol. 2007 Apr;18(4):1046-56
references.pmid: 17360947
references.citation: J Exp Med. 2001 Jun 4;193(11):F41-6
references.pmid: 11390442
references.citation: Am J Transplant. 2010 Nov;10(11):2410-20
references.pmid: 20977632
references.citation: J Clin Invest. 2010 Jun;120(6):1836-47
references.pmid: 20501946
references.citation: Am J Transplant. 2011 Mar;11(3):450-62
references.pmid: 20973913
references.citation: J Clin Invest. 2010 Jun;120(6):1848-61
references.pmid: 20501943
references.citation: J Immunol. 2009 Aug 1;183(3):1518-22
references.pmid: 19570829
references.citation: Lancet. 2011 Oct 15;378(9800):1428-37
references.pmid: 22000139
references.citation: Am J Transplant. 2007 Feb;7(2):408-15
references.pmid: 17229080
references.citation: Kidney Int. 2014 Mar;85(3):590-9
references.pmid: 24284517
references.citation: J Am Soc Nephrol. 2003 Jun;14(6):1643-51
references.pmid: 12761267
references.citation: Transplantation. 2010 Jul 15;90(1):68-74
references.pmid: 20463643
references.citation: Front Immunol. 2013 Dec 31;4:497
references.pmid: 24427159
references.citation: Am J Transplant. 2012 May;12(5):1157-67
references.pmid: 22429309
references.citation: Am J Transplant. 2012 Feb;12(2):388-99
references.pmid: 22081892
references.citation: Health Policy. 1998 Jun;44(3):215-32
references.pmid: 10182294
references.citation: Am J Transplant. 2012 Mar;12(3):640-8
references.pmid: 22151236