title: Impaired direct priming of CD8 T cells by donor-derived cytomegalovirus following kidney transplantation.
abstract: Cytomegalovirus (CMV) infection increases the risk of complications after renal transplantation, but the mechanisms controlling donor-derived infection are not adequately characterized. Here, we assessed the risk of clinically significant CMV disease in donor-seropositive, recipient-seropositive (D+R+) renal transplantation and examined recipients' CMV antigen-specific cellular immune responses primed directly by donor cells. In a retrospective cohort of 569 patients administered standardized basiliximab-tacrolimus-mycophenolate-corticosteroid immunosuppressive therapy, CMV disease rates increased in D+R+ serostatus pairings compared with D-R+ pairings (hazard ratio [HR], 2.61; 95% confidence interval [CI], 1.36 to 5.01; P=0.004) and associated with increased donor-recipient HLA mismatch in the D+R+ group (HR [per class 1 mismatch], 1.43; 95% CI, 1.12 to 1.82]; P=0.02). D+R+ and D+R- transplants in which the donor and recipient differentially expressed at least one HLA class I allele were followed prospectively from the time of transplantation. During the first year after transplantation, four of eight seropositive recipients and one of three seronegative recipients displayed peripheral blood CD8+ T cell responses to CMV presented by recipient-specific HLA. Notably, no recipients mounted responses to CMV presented by donor-specific HLA, despite the detection of CMV antigen expression in all seropositive donor organs examined (n=10), suggesting that the allograft of Class I HLA-mismatched seropositive donors is inaccessible to CD8+ T cell responses. Finally, pretransplant assays of anti-CMV cellular immunity predicted post-transplant CMV replication less accurately in D+R+ pairings than in D-R+ pairings, possibly reflecting in vitro assay specificity for recipient, rather than donor, HLA. These findings are relevant to the clinical management and immunologic understanding of donor-transmitted viral infection.
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital Birmingham.
authors.forename: Shazia
authors.initials: S
authors.lastname: Shabir
authors.forename: Baksho
authors.initials: B
authors.lastname: Kaul
authors.forename: Annette
authors.initials: A
authors.lastname: Pachnio
authors.forename: Gemma D
authors.initials: GD
authors.lastname: Banham
authors.forename: Helen
authors.initials: H
authors.lastname: Smith
authors.forename: Sourabh
authors.initials: S
authors.lastname: Chand
authors.forename: Seema
authors.initials: S
authors.lastname: Jham
authors.forename: Lorraine
authors.initials: L
authors.lastname: Harper
authors.forename: Simon
authors.initials: S
authors.lastname: Ball
authors.forename: Afsar
authors.initials: A
authors.lastname: Rahbar
authors.forename: Cecilia
authors.initials: C
authors.lastname: Söderberg-Nauclér
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.forename: Richard
authors.initials: R
authors.lastname: Borrows
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D003587:Cytomegalovirus / Q000276:immunology* / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005805:Genes, MHC Class I / Q000276:immunology; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology / Q000821:virology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011183:Postoperative Complications / Q000276:immunology / Q000821:virology*; D011446:Prospective Studies; D012189:Retrospective Studies
chemical_list: D018984:Epitopes, T-Lymphocyte