CORRECTION OF ABNORMAL T-CELL RECEPTOR REPERTOIRE DURING INTERFERON-ALPHA THERAPY IN PATIENTS WITH DAIRY CELL LEUKEMIA

Patients with the B-cell malignancy hairy cell leukemia (HCL) exhibit a skewed T-cell repertoire with oligoclonal expression or absence of m any members of the T-cell receptor (TCR) BV gene families. To evaluate whether interferon-alpha (IFN-alpha) therapy would not only restore n ormal hematopoiesis, but also the abnormal T-cell repertoire, we studi ed 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 IF N-alpha treatment. The junctional regions from 22 TCRBV gene families were analyzed after polymerase chain reaction amplification of cDNA (R T-PCR) using family specific primers. In all seven patients improvemen t of the skewed T-cell repertoire was not seen until 2 years of treatm ent. It consisted of disappearance of oligoclonal subpopulations and ( polyclonal) reappearance of absent TCRBV gene families. The RT-PCR res ults were correlated with the TCRBV protein expression using TCRBV-spe cific monoclonal antibodies. T lymphocytes from four patients with act ive HCL contained large expansions of particular TCRBV-expressing cell s (up to 25% of the CD3(+) cells; 600 to 700/mu L whole blood), which decreased during IFN-alpha therapy in both patients tested. Finally, r estoration of the TCR repertoire matched normalization of the function al immune repertoire as measured by proliferative, helper, and cytotox ic T-lymphocyte precursor frequencies against major histocompatibility complex-unrelated individuals. In conclusion, oligoclonal bands of TC RBV gene families found by RT-PCR correspond with a dramatic increase in circulating T lymphocytes expressing the same TCRBV family. Moreove r, IFN-alpha can restore the skewed T-cell repertoire and suppress per sistent T-cell clones upon treatment of the accompanying malignancy. ( C) 1998 by The American Society of Hematology.