Normalization of skewed T cell repertoire by interferon-α 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-α (IFN-α) 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-α in the past, at initiation, and at several intervals up to 6 years of IFN-α 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/μL whole blood), which decreased during IFN-α 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-α can restore the skewed T-cell repertoire and suppress persistent T-cell clones upon treatment of the accompanying malignancy.

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Persistent clonal excess and skewed T-cell repertoire in T cells from patients with hairy cell leukemia

Blood ◽

10.1182/blood.v87.9.3795.bloodjournal8793795 ◽

1996 ◽

Vol 87 (9) ◽

pp. 3795-3802 ◽

Cited By ~ 51

Author(s):

JC Kluin-Nelemans ◽

MG Kester ◽

JJ Melenhorst ◽

JE Landegent ◽

L van de Corput ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hairy Cell Leukemia ◽

T Cell Subsets ◽

Cell Populations ◽

T Cell Repertoire ◽

Hairy Cell ◽

Cell Leukemia ◽

Cell Repertoire ◽

Blood Samples

Hairy cell leukemia (HCL) is characterized by a severe T-cell-mediated immune deficiency. At the same time, spontaneous T-cell activation is noted when splenic T cells are studied in vivo and in vitro. Therefore, we searched for oligoclonal T-cell populations in the blood and spleens of 25 patients with HCL using a T-cell receptor gamma-polymerase chain reaction (TCR gamma-PCR). Subsequently, in 6 patients, the CDR3 length and conformation from 22 different TCRBV subfamilies were analyzed after PCR amplification of cDNA using TCRBV subfamily-specific primers. T cells from 15 of 25 HCL patients showed clonal excess by the TCR gamma-PCR. In fluorescence-activated cell sorted T-cell subsets, more clonal bands were observed than in the unseparated T cells, with most of these in CD8+ subsets, but also in CD4+, CD3+ gamma/delta+, and a double-negative CD3+ alpha/beta+ subset. In other B-cell malignancies, 6 of 16 samples showed oligoclonal T cells, whereas only 2 of 18 normal spleen and blood samples showed abnormal bands. Analysis of the TCRBV subfamilies disclosed in all 6 HCL patients a markedly abnormal pattern, with many clonal bands in 5 to 15 subfamilies, and absent or abnormal weak patterns in another 1 to 8 subfamilies. In comparison, 6 normal samples (2 spleens and 4 blood samples) showed in only 1 blood donor 1 clonal band. Two patients with active HCL but without infections or treatment were tested several times during the course of the disease and showed a complete identical skewed T-cell repertoire with the same oligoclonal T-cell populations. In conclusion, T cells in the blood and spleen of HCL patients show impressive abnormalities with many oligoclonal T-cell populations and a very restricted and skewed TCRBV repertoire.

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Correction of Abnormal T-Cell Receptor Repertoire During Interferon-α Therapy in Patients With Hairy Cell Leukemia

Blood ◽

10.1182/blood.v91.11.4224.411k19_4224_4231 ◽

1998 ◽

Vol 91 (11) ◽

pp. 4224-4231 ◽

Cited By ~ 2

Author(s):

Hanneke C. Kluin-Nelemans ◽

Michel G.D. Kester ◽

Lisette van deCorput ◽

Patrick P.C. Boor ◽

Jim E. Landegent ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Gene Families ◽

Cell Receptor ◽

Interferon Α ◽

T Cell Repertoire ◽

Hairy Cell ◽

Cell Leukemia ◽

Rt Pcr ◽

Cell Repertoire

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-α (IFN-α) 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-α in the past, at initiation, and at several intervals up to 6 years of IFN-α 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/μL whole blood), which decreased during IFN-α 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-α can restore the skewed T-cell repertoire and suppress persistent T-cell clones upon treatment of the accompanying malignancy.

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Characterization of T-cell repertoire in hairy cell leukemia patients before and after recombinant immunotoxin BL22 therapy

Cancer Immunology Immunotherapy ◽

10.1007/s00262-005-0099-1 ◽

2005 ◽

Vol 55 (9) ◽

pp. 1100-1110 ◽

Cited By ~ 13

Author(s):

Evgeny Arons ◽

Lynn Sorbara ◽

Mark Raffeld ◽

Maryalice Stetler-Stevenson ◽

Seth M. Steinberg ◽

...

Keyword(s):

T Cell ◽

Hairy Cell Leukemia ◽

T Cell Repertoire ◽

Hairy Cell ◽

Cell Leukemia ◽

Cell Repertoire ◽

Recombinant Immunotoxin ◽

Before And After

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Response duration and recovery of CD4+ lymphocytes following deoxycoformycin in interferon-α-resistant hairy cell leukemia: 7-year follow-up

Leukemia ◽

10.1038/sj.leu.2400513 ◽

1997 ◽

Vol 11 (1) ◽

pp. 42-47 ◽

Cited By ~ 47

Author(s):

JF Seymour ◽

M Talpaz ◽

R Kurzrock

Keyword(s):

Hairy Cell Leukemia ◽

Response Duration ◽

Interferon Α ◽

Hairy Cell ◽

Cell Leukemia ◽

Cd4 Lymphocytes

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Hairy cell leukemia: a tumor of pre-plasma cells

Blood ◽

10.1182/blood.v65.3.620.bloodjournal653620 ◽

1985 ◽

Vol 65 (3) ◽

pp. 620-629 ◽

Cited By ~ 1

Author(s):

KC Anderson ◽

AW Boyd ◽

DC Fisher ◽

D Leslie ◽

SF Schlossman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Plasma Cell ◽

Hairy Cell Leukemia ◽

Plasma Cells ◽

Tartrate Resistant Acid Phosphatase ◽

Hairy Cell ◽

Cell Leukemia ◽

Cell Surface Antigens ◽

Hairy Cells

Monoclonal antibodies defining B-, T-, and myeloid-restricted cell surface antigens were used to characterize the lineage and state of differentiation of tumor cells isolated from 22 patients with hairy cell leukemia (HCL). These tumors were shown to be of B lineage because they strongly expressed the B cell-restricted antigens B1 and B4 and lacked T cell- and monocyte-restricted antigens. Moreover, the strong expression of the plasma cell-associated PCA-1 antigen on the majority of hairy cells suggested that these tumors correspond to later stages of B cell ontogeny. Dual fluorescence experiments further confirmed that HCL splenocytes that coexpressed B1 and PCA-1 demonstrated both the morphology and tartrate-resistant acid phosphatase positivity of hairy cells. The observation that some hairy cells either spontaneously produce immunoglobulin (Ig) or could be induced to proliferate and secrete Ig provides complementary support for the view that HCL is a pre-plasma cell tumor. However, staining of hairy cells with anti-IL2R1 monoclonal antibody, which is directed to the T cell growth factor receptor and/or with the anti-Mo1 reagent, directed to C3bi complement receptor, distinguish these cells from currently identified B cells.

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Rearrangement of both immunoglobulin and T-cell receptor genes in a prolymphocytic variant of hairy cell leukemia patient resistant to interferon-alpha [published erratum appears in Blood 1989 Feb;73(2):624]

Blood ◽

10.1182/blood.v72.5.1708.bloodjournal7251708 ◽

1988 ◽

Vol 72 (5) ◽

pp. 1708-1716

Author(s):

SL Giardina ◽

HA Young ◽

CR Faltynek ◽

ES Jaffe ◽

JW Clark ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Peripheral Blood ◽

Hairy Cell Leukemia ◽

Cell Receptor ◽

Hairy Cell ◽

Cell Leukemia ◽

Ifn Gamma ◽

Ifn Alpha ◽

Alpha Receptors

We describe a patient with the so-called “prolymphocytic variant” form of hairy cell leukemia (HCL) resistant to treatment with interferon- alpha (IFN-alpha). Analysis of immunoglobulin (Ig) and T-cell receptor- beta (TCR beta) gene rearrangements from serial peripheral blood mononuclear cell specimens (MNCs) confirmed not only the B-cell nature of the disease, but also the subsequent emergence of a morphologically indistinguishable population of cells with a clonal TCR beta rearrangement in addition to the original Ig gene rearrangement. With the exception of a transient increase in peripheral blood T cells during treatment with deoxycoformycin (DCF), the MNCs remained essentially constant throughout therapy with no evidence of a co- existing T-cell clone to account for the TCR beta rearrangement. Although MNCs from this patient bound significantly less IFN-alpha than did MNCs from other HCL patients, the binding was of high affinity with a kd similar to that of control cells. The number of IFN-gamma receptors on our patient's MNCs was four times higher than the number of IFN-alpha receptors and was similar to the number of IFN-alpha receptors on MNCs from HCL patients responsive to IFN-alpha. While various treatments including IFN-alpha, DCF, chlorambucil, splenectomy, leukopheresis, and IFN-gamma were not able to change the clinical progression of the disease, they may have provided an opportunity for the divergent TCR beta rearranged clone to expand and displace the initially dominant clone.

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