title: Major histocompatibility complex class I-related chain A allele mismatching, antibodies, and rejection in renal transplantation.
abstract: Even when kidney allografts are well matched for human leukocyte antigen (HLA) and anti-HLA antibodies are not detected, graft rejection can still occur. There is evidence that some patients who lose their graft have antibodies specific for major histocompatibility complex (MHC) class I-related chain A (MICA) antigens. We investigated whether mismatching MICA alleles associates with MICA antibody production and graft rejection or dysfunction. MICA and HLA antibody screening in 442 recipients was performed, and specificities were confirmed in a subgroup of 227 recipients using single-antigen multiplex technology. For assignment of MICA antibody specificity, we used three independent assays. In addition, MICA alleles of 227 recipients and donors were determined by DNA sequencing. In all, 17 patients (7.5%) had MICA antibodies, and 13 patients (6%) developed MICA donor-specific antibodies (DSA). Multivariate analysis revealed MICA mismatching, as an independent significant factor associated with the presence of MICA antibodies (p = 0.009), and 14 mismatched MICA residues significantly correlated with MICA antibody production. MICA and HLA antibodies significantly associated with acute rejection (AR) and MICA DSA and HLA DSA correlated with decreased graft function by univariate and multivariate analysis. We conclude that mismatching for MICA epitopes in renal transplantation is a mechanism leading to production of MICA antibodies that associate with AR and graft dysfunction.
authors.affiliation: Anthony Nolan Research Institute, London, United Kingdom. steven.cox@anthonynolan.org.uk
authors.forename: Steven T
authors.initials: ST
authors.lastname: Cox
authors.forename: Henry A F
authors.initials: HA
authors.lastname: Stephens
authors.forename: Raymond
authors.initials: R
authors.lastname: Fernando
authors.forename: Aliyye
authors.initials: A
authors.lastname: Karasu
authors.forename: Mark
authors.initials: M
authors.lastname: Harber
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Howie
authors.forename: Stephen
authors.initials: S
authors.lastname: Powis
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Zou
authors.forename: Peter
authors.initials: P
authors.lastname: Stastny
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: Madrigal
authors.forename: Ann-Margaret
authors.initials: AM
authors.lastname: Little
mesh_terms: D000328:Adult; D000483:Alleles; D000918:Antibody Specificity / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000097:blood*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007518:Isoantibodies / Q000097:blood / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies; C099187:MHC class I-related chain A