title: Alloimmune responses and atherosclerotic disease after kidney transplantation.
abstract: BACKGROUND
  Chronic exposure to exogenous antigens causes accumulation of proinflammatory CD57(+)CD28(-) hyperactivated CD8(+) T cells that may promote atherosclerosis. We hypothesized that persistent alloimmune responses may induce immune activation and contribute to posttransplant atherosclerosis.
  
  
  METHODS
  This hypothesis was tested in a single-center cohort of 577 kidney transplant patients. Propensity score analysis was performed to address potential confounding variables by indication. Immune exhaustion was studied in subcohort of 103 patients.
  
  
  RESULTS
  Five hundred seventy-seven consecutive renal transplant recipients were included. Seventy-seven atherosclerotic events (AE) (12.3%) occurred during a mean follow-up of 7 years. The cumulative incidence of AE increased with the number of human leukocyte antigen (HLA) mismatches (18%, 10%, and 5% in patients with 5-6, 3-4, and 0-2 mismatches, respectively; P=0.012). Human leukocyte antigen mismatch number (hazards ratio, 1.35; 95% confidence interval, 1.10-1.66, for each supplementary mismatch; P=0.005) was an independent risk factor for AE. In the propensity score match analysis, having received a well-matched kidney conferred a reduced risk of AE (hazards ratio, 0.22; 95% confidence interval, 0.05-0.95; P=0.044). We observed a significant correlation between HLA mismatch numbers and circulating CD57(+)CD28(-) CD8(+) T cells (R=0.31; P=0.017). These CD8(+) T cells were more frequent in patients with more HLA mismatches (P<0.0001).
  
  
  CONCLUSIONS
  Overall, our results suggest that chronic allogeneic stimulation participates to accelerated atherosclerosis observed after transplantation.
authors.affiliation: 1 INSERM, UMR1098, FHU INCREASE (Integrated Centre for Research in Inflammatory Diseases), LabEX LipSTIC, Besançon, France. 2 Université de Franche-Comté, Besançon, France. 3 SFR FED4234, Besançon, France. 4 Department of Nephrology, Dialysis, and Renal Transplantation, CHU Besançon, Besançon, France. 5 CHU Besançon, CIC-BT 506, Besançon, France. 6 EFS Bourgogne Franche-Comté, CIC-BT 506, Plateforme de Biomonitoring, Besançon, France. 7 Department of Nephrology, Dialysis, and Renal Transplantation, CHU Dijon, FHU INCREASE, LabEX LipSTIC, Dijon, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Ducloux
authors.forename: Cécile
authors.initials: C
authors.lastname: Courivaud
authors.forename: Jamal
authors.initials: J
authors.lastname: Bamoulid
authors.forename: Vincent
authors.initials: V
authors.lastname: Bisaccia
authors.forename: Caroline
authors.initials: C
authors.lastname: Roubiou
authors.forename: Thomas
authors.initials: T
authors.lastname: Crepin
authors.forename: Béatrice
authors.initials: B
authors.lastname: Gaugler
authors.forename: Caroline
authors.initials: C
authors.lastname: Laheurte
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rebibou
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Chalopin
authors.forename: Philippe
authors.initials: P
authors.lastname: Saas
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D018106:CD28 Antigens / Q000097:blood; D018959:CD57 Antigens / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D015986:Confounding Factors, Epidemiologic; D018572:Disease-Free Survival; D005260:Female; D005602:France / Q000453:epidemiology; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006650:Histocompatibility Testing; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000009:adverse effects*; D016015:Logistic Models; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D057216:Propensity Score; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors
chemical_list: D015415:Biomarkers; D018106:CD28 Antigens; D018959:CD57 Antigens; D006680:HLA Antigens