title: Interleukin-2 receptor blockade in cardiac transplantation: influence of HLA-DR locus incompatibility on treatment efficacy.
abstract: BACKGROUND
  Because allograft rejection results from specific T-cell activation by donor human leukocyte antigens (HLA), new immunomodulatory therapies for organ-transplant recipients are used to selectively block T-cell activity without global immunosuppression. We investigated whether blockade of the high-affinity interleukin (IL)-2 receptor effectively prevented T-cell alloreactivity in cardiac transplantation.
  
  
  RESULTS
  A study of a humanized monoclonal antibody against the high-affinity IL-2 receptor (daclizumab) was performed in 70 adult, cardiac-transplant recipients. Patients were stratified based on the degree of donor-recipient HLA-DR matches. Primary and secondary endpoints were incidence and frequency of high-grade allograft rejections, IL-2-dependent, T-cell outgrowth from biopsy sites as measured by lymphocyte growth assay, and production of anti-HLA antibodies. Treatment with daclizumab significantly prevented development of high-grade acute rejection in recipients with at least one donor HLA-DR locus match during the first 3 months posttransplantation; in this group 0 of 13 (0%) treated with daclizumab experienced at least one high-grade rejection versus 3 of 13 (23%) controls (P=0.05). In addition, 1 of 12 (9%) daclizumab-treated patients experienced one or more episodes of IL-2-dependent, T-cell outgrowth versus 5 of 12 (42%) patients in the untreated group (P=0.05). In contrast, daclizumab used at the same dose and schedule was not as effective in fully HLA-DR-mismatched recipients. After cessation of daclizumab, allograft rejection increased to levels seen in controls.
  
  
  CONCLUSIONS
  IL-2-receptor blockade is effective for preventing alloreactivity and high-grade rejection in cardiac transplantation; however, its efficacy seemed to be influenced by the degree of donor-recipient, HLA-DR locus mismatching.
authors.affiliation: Transplantation Immunology, Department of Surgery, Columbia-Presbyterian Medical Center, New York, NY 10032, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lietz
authors.forename: Ranjit
authors.initials: R
authors.lastname: John
authors.forename: Ainat
authors.initials: A
authors.lastname: Beniaminovitz
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Burke
authors.forename: Nicole
authors.initials: N
authors.lastname: Suciu-Foca
authors.forename: Donna M
authors.initials: DM
authors.lastname: Mancini
authors.forename: Niloo M
authors.initials: NM
authors.lastname: Edwards
authors.forename: Silviu
authors.initials: S
authors.lastname: Itescu
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000077561:Daclizumab; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D012189:Retrospective Studies; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006684:HLA-DR Antigens; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D000077561:Daclizumab