title: Replacement therapy with plasma-derived factor VIII concentrates induces skew in T-cell receptor usage and clonal expansion of CD8+ T-cell in HIV-seronegative hemophilia patients.
abstract: Replacement therapy with factor VIII (FVIII) products causes immune abnormalities in human immunodeficiency virus (HIV)-seronegative hemophilia patients. However, the question remains why an absolute increase in the number of CD8+ T-cells and diminished proliferation responses of lymphocytes to antigen stimulation in vitro occurs in HIV-seronegative hemophilia patients. To examine whether the FVIII products induce skewing of T-cell receptor (TCR) repertoires, TCR variable region alpha-chain and beta-chain repertoires were analyzed for peripheral blood mononuclear cells (PBMCs) from 15 hemophilia patients treated with heated and/or non-heated plasma-derived FVIII concentrates and 10 age-matched healthy adults. Also, T-cell clonality was compared between these groups using complementarity-determining region 3 (CDR3) size spectratyping. The skewing of TCR repertoires was significantly greater for hemophilia patients than healthy controls. The extent of T-cell clonality was greater for hemophilia patients than the controls, indicating that clonal T-cells frequently expanded in hemophilia patients. The skew in TCR usage and clonal expansion were primarily observed in patients treated with non-heated plasma-derived products. The spectratyping and sequencing of CDR3 regions revealed that the clonal expansion of T-cells was observed for CD8+ T-cells, but not CD4+ T-cells. These results suggest that extensive expansion of CD8+ T-cells is induced by some viruses other than HIV present in FVIII preparations, and the resulting accumulation of CD8+ T-cells is responsible for changes in peripheral T-cell population in HIV-seronegative hemophilia patients.
authors.affiliation: Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Matsutani
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tsuruta
authors.forename: Ryuji
authors.initials: R
authors.lastname: Suzuki
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshioka
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology*; D016022:Case-Control Studies; D002455:Cell Division; D002648:Child; D002999:Clone Cells / Q000473:pathology; D022801:Complementarity Determining Regions; D005169:Factor VIII / Q000009:adverse effects* / Q000627:therapeutic use*; D018023:HIV Seronegativity; D006467:Hemophilia A / Q000628:therapy* / Q000821:virology; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000097:blood*
chemical_list: D022801:Complementarity Determining Regions; D016693:Receptors, Antigen, T-Cell, alpha-beta; D005169:Factor VIII