title: Correction of abnormal T-cell receptor repertoire during interferon-alpha therapy in patients with hairy cell leukemia.
abstract: Patients with the B-cell malignancy hairy cell leukemia (HCL) exhibit a skewed T-cell repertoire with oligoclonal expression or absence of many members of the T-cell receptor (TCR) BV gene families. To evaluate whether interferon-alpha (IFN-alpha) therapy would not only restore normal hematopoiesis, but also the abnormal T-cell repertoire, we studied T lymphocytes from a cohort of HCL patients treated by IFN-alpha in the past, at initiation, and at several intervals up to 6 years of IFN-alpha treatment. The junctional regions from 22 TCRBV gene families were analyzed after polymerase chain reaction amplification of cDNA (RT-PCR) using family specific primers. In all seven patients improvement of the skewed T-cell repertoire was not seen until 2 years of treatment. It consisted of disappearance of oligoclonal subpopulations and (polyclonal) reappearance of absent TCRBV gene families. The RT-PCR results were correlated with the TCRBV protein expression using TCRBV-specific monoclonal antibodies. T lymphocytes from four patients with active HCL contained large expansions of particular TCRBV-expressing cells (up to 25% of the CD3+ cells; 600 to 700/microL whole blood), which decreased during IFN-alpha therapy in both patients tested. Finally, restoration of the TCR repertoire matched normalization of the functional immune repertoire as measured by proliferative, helper, and cytotoxic T-lymphocyte precursor frequencies against major histocompatibility complex-unrelated individuals. In conclusion, oligoclonal bands of TCRBV gene families found by RT-PCR correspond with a dramatic increase in circulating T lymphocytes expressing the same TCRBV family. Moreover, IFN-alpha can restore the skewed T-cell repertoire and suppress persistent T-cell clones upon treatment of the accompanying malignancy.
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H C
authors.initials: HC
authors.lastname: Kluin-Nelemans
authors.forename: M G
authors.initials: MG
authors.lastname: Kester
authors.forename: L
authors.initials: L
authors.lastname: van deCorput
authors.forename: P P
authors.initials: PP
authors.lastname: Boor
authors.forename: J E
authors.initials: JE
authors.lastname: Landegent
authors.forename: J J
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: R
authors.initials: R
authors.lastname: Willemze
authors.forename: J H
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017252:CD3 Complex / Q000032:analysis; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism*; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000627:therapeutic use*; D007943:Leukemia, Hairy Cell / Q000097:blood* / Q000188:drug therapy*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D017252:CD3 Complex; D007135:Immunoglobulin Variable Region; D016898:Interferon-alpha; D016693:Receptors, Antigen, T-Cell, alpha-beta