title: Aortic valve allograft structural deterioration is associated with a subset of antibodies to human leukocyte antigens.
abstract: OBJECTIVE
  The association between aortic valve allograft dysfunction in patients with long-term follow up and human leukocyte class 2 antigen donor/recipient mismatch suggests that elements of the anti-donor immune response penetrate and damage the aortic valve allograft. An aortic valve allograft recipient cohort was studied to determine whether presence of recipient antibodies to donor human leukocyte class 1 or 2 antigen was associated with shorter time to aortic valve allograft dysfunction.
  
  
  METHODS
  Both donor and recipient human leukocyte antigen (HLA) type, HLA antibody information and echocardiography data were available for 148 recipients of cryopreserved aortic valve allografts between 1986 and 1998. Structural deterioration of the aortic valve allograft was defined as at least moderate aortic stenosis or regurgitation by echocardiography. Recipient sera were assayed for anti-HLA (class 1 and 2) antibodies using three assays: complement-dependent cytotoxicity (CDC) on T- and B-lymphocyte panels (CDC PRA); flow cytometry using HLA-coated beads (Flow PRA); and an ELISA using HLA-coated microwells. The donor specificity of anti-class 1 and 2 HLA antibodies was determined on T- and B-cell panels using CDC. Associations between the results of the three assays and donor-specific class 1 and 2 antibodies and time to structural deterioration were analyzed using Kaplan-Meier curves of freedom from structural deterioration. Cox proportional-hazards were used to determine independent predictors of time to structural deterioration.
  
  
  RESULTS
  Patients highly positive for HLA class 2 antibodies using an ELISA had a significant association (p = 0.007) with shorter time to aortic valve allograft structural deterioration using both a log rank test and Cox proportional-hazards analysis. Patients (n = 15) with donor-specific antibodies to class 2 antigen (DR antigens) had significantly more structural deterioration (p = 0.035) than those without specific antibodies.
  
  
  CONCLUSIONS
  The association between aortic valve allograft structural deterioration and high titer human leukocyte class 2 antigen antibodies, a subset detected by ELISA adds further information about the link between HLA class 2 mismatch and structural deterioration. Further studies are needed to confirm the importance of class 2 antibodies on outcome, and to determine by which method these antibodies should be detected. Potential recipients with pre-existing antibodies of these specific types might be expected to sustain accelerated allograft damage.
authors.affiliation: Department of Cardiothoracic Surgery and Clinical Research Center, Vanderbilt University, Nashville, TN, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dignan
authors.forename: Mark
authors.initials: M
authors.lastname: O'Brien
authors.forename: Patrick
authors.initials: P
authors.lastname: Hogan
authors.forename: Alycia
authors.initials: A
authors.lastname: Thornton
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fowler
authors.forename: Daniel
authors.initials: D
authors.lastname: Byrne
authors.forename: Fiona
authors.initials: F
authors.lastname: Stephens
authors.forename: Susan
authors.initials: S
authors.lastname: Harrocks
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001021:Aortic Valve / Q000276:immunology / Q000637:transplantation*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D015925:Cryopreservation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D006680:HLA Antigens / Q000032:analysis; D006684:HLA-DR Antigens / Q000032:analysis; D006349:Heart Valve Diseases / Q000601:surgery*; D000949:Histocompatibility Antigens Class II / Q000032:analysis / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011336:Probability; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D014019:Tissue Donors; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
chemical_list: D006680:HLA Antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II