title: Alterations of T cell receptor Vbeta repertoire of CD8 T lymphocytes in immune tolerance induction in two hemophilia A patients with inhibitors.
abstract: OBJECTIVE
  Hemophilia A patients with inhibitors are treated effectively with immune tolerance induction (ITI) therapy. Although anti-idiotypic antibodies may play a certain role in the underlying mechanism, the detailed mechanism by which ITI produces a curative effect remains unknown. The aim of this study was to clarify the immunological aspect of ITI.
  
  
  METHODS
  Longitudinal T-cell receptor (TCR) analysis was performed during ITI. TCR variable region alpha-chain and beta-chain repertoires were serially analyzed for peripheral blood mononuclear cells (PBMCs), CD4 T cells, and CD8 T cells from 2 hemophilia inhibitor patients treated with ITI (Patients 1 and 2). Furthermore, to see whether skewing observed in TCR analysis resulted from clonality alterations, T cell clonality was investigated using complementarity-determining region 3 (CDR3) size spectratyping.
  
  
  RESULTS
  In the patient 1, inhibitor titer remained to be 19.6 BU/mL for 596 days after ITT commencement, and ITI was unsuccessful. In the patient 2, inhibitor titer disappeared 434 days after ITI commencement, and ITI was successful. In both cases, skewing of TCR variable region alpha/beta-chain repertoires was observed in CD8 T cell subset, whereas not in CD4 T cell subset.
  
  
  CONCLUSIONS
  Alteration of TCR repertoires, especially TCR variable region beta-chain repertoire of CD8 T cells, was distinct between successful and unsuccessful cases, suggesting that immunological response in the early phase affected the ITI outcomes.
authors.affiliation: Nara Medical University School of Medicine, Department of Pediatrics, Kashihara, Japan. ysakurai@naramed-u.ac.jp
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Takaji
authors.initials: T
authors.lastname: Matsutanit
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshioka
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
mesh_terms: D019774:Blood Coagulation Factor Inhibitors / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D006467:Hemophilia A / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007223:Infant; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; D005169:Factor VIII