title: The avidity, not the mere presence, of primed cytotoxic T-lymphocytes for donor human leukocyte class II antigens determines their clinical relevance after heart transplantation.
abstract: BACKGROUND
  To analyze the relevance of CD4-positive cytotoxic T-lymphocytes (CTL) in clinical heart rejection, we studied the frequency and avidity of donor human leukocyte antigen class II-specific CTL present within the graft during a rejection episode and during a period without rejection.
  
  
  METHODS
  For this analysis endomyocardial biopsies of heart transplant recipients were cultured to obtain graft-infiltrating lymphocytes (GIL). GIL cultures exhibiting donor class II-directed cytotoxicity were considered for this study. With limiting dilution analysis, the frequency of donor class II-specific CTL that had been primed by donor antigens in vivo (designated cCTL) was determined in GIL cultures established from endomyocardial biopsies taken during a rejection episode (n = 10) or during a period without rejection (n = 11). Addition of anti-CD4 to the limiting dilution analysis revealed the fraction of donor class II-specific cCTL having a high avidity for donor antigen.
  
  
  RESULTS
  During a rejection episode, 196 (median) donor class II-specific cCTL/106 GIL were present. In a period without rejection, the frequency of donor class II-specific cCTL was not significantly different (median = 330/10(6); p = 0.1). Addition of anti-CD4, however, revealed that donor class II-specific cCTL with a high avidity for donor antigen are predominant during a rejection episode (median = 100%) but are in minority during a period without rejection (median = 35%; p < 0.0001).
  
  
  CONCLUSIONS
  These results suggest that graft-infiltrating CD4+ CTL can mediate heart rejection provided they have a high avidity for donor antigen.
authors.affiliation: Department of Internal Medicine I, University Hospital Rotterdam-Dijkzigt, The Netherlands.
authors.forename: N E
authors.initials: NE
authors.lastname: van Emmerik
authors.forename: E H
authors.initials: EH
authors.lastname: Loonen
authors.forename: L M
authors.initials: LM
authors.lastname: Vaessen
authors.forename: A H
authors.initials: AH
authors.lastname: Balk
authors.forename: B
authors.initials: B
authors.lastname: Mochtar
authors.forename: F H
authors.initials: FH
authors.lastname: Claas
authors.forename: W
authors.initials: W
authors.lastname: Weimar
mesh_terms: D000915:Antibody Affinity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000939:Epitopes; D000949:Histocompatibility Antigens Class II