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

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3795-3802 ◽  
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.

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

2005 ◽  
Vol 55 (9) ◽  
pp. 1100-1110 ◽  
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

Normalization of skewed T cell repertoire by interferon-α therapy in patients with hairy cell leukemia

1997 ◽  
Vol 56 ◽  
pp. 456
Author(s):  
M.G.D. Kester ◽  
L. van de Corput ◽  
P.P.C. Boor ◽  
J.E. Landegent ◽  
J.J.M. van Dongen ◽  
...  
Keyword(s):  
T Cell ◽  
Hairy Cell Leukemia ◽  
Interferon Α ◽  
T Cell Repertoire ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Cell Repertoire

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

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4224-4231 ◽  
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

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.

scholarly journals B-ly-7, a monoclonal antibody reactive with hairy cell leukemia, also defines an activation antigen on normal CD8+ T cells [see comments]

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 959-964 ◽  
Author(s):  
SP Mulligan ◽  
P Travade ◽  
E Matutes ◽  
C Dearden ◽  
L Visser ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Hairy Cell Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Activation Antigen

Abstract We undertook a study to determine the specificity of the monoclonal antibody, B-ly-7, for hairy cell leukemia (HCL) by examining the expression in 150 samples from B-cell lymphoproliferative diseases as well as screening for reactivity in a number of other hematologic malignancies. Within the B-cell lineage we found that the expression of B-ly-7 was highly specific for HCL and reacted with all 28 cases examined, as well as with 3 of 9 cases of a variant form of HCL. Cells of other closely related B-cell disorders, prolymphocytic leukemia, and splenic lymphoma with villous lymphocytes were negative. Investigation of the peripheral blood and bone marrow of patients with HCL before and after treatment with alpha-interferon or deoxycoformycin suggests that B-ly-7 may be useful in the assessment of minimal disease after therapy. In addition to HCL, we found that B-ly-7 was positive with cells of three mature, CD4+ T-cell malignancies. In view of the reactivity with malignancies of activated B and T cells, we searched for the expression of B-ly-7 on activated, normal B and T cells and found that B-ly-7 reacted specifically with activated normal peripheral blood CD8+ T cells. B-ly-7 has a number of applications, including the precise classification of mature B-cell neoplasia and the diagnosis HCL and its assessment after treatment. In addition, B-ly-7 recognizes a small subset of T-cell disorders. Its expression on these malignancies and on in vitro activated peripheral blood CD8+ T cells suggests that B- ly-7 detects a lymphocyte activation antigen.

Hairy Cell Leukemia-Specific Recognition by Multiple Autologous HLA-DQ or DP-Restricted T-Cell Clones

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 251-259
Author(s):  
Lisette van de Corput ◽  
Hanneke C. Kluin-Nelemans ◽  
Michel G.D. Kester ◽  
Roel Willemze ◽  
J.H. Frederik Falkenburg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hairy Cell Leukemia ◽  
Lymphoblastic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
T Cell Clones ◽  
Cell Clones ◽  
Hla Dq ◽  
T Cell Clone

We studied in patients with hairy cell leukemia (HCL) whether autoreactive T cells could be isolated with specific reactivity to the HCL cells. HCL cells were activated via triggering of CD40 on the cell membrane and used as stimulator cells to generate autologous T-cell clones. Two types of CD4+BV2+ T-cell clones with different CDR3 rearrangements and one type of CD4+BV8S3+ T-cell clone were generated from the spleen or blood. These clones specifically recognized the autologous HCL cells, without reactivity to autologous peripheral blood mononuclear cells (PBMC), phytohemagglutinin blasts, or Epstein-Barr virus–transformed B cells in a primed lymphocyte test. Blocking and panel studies using HCL cells from 11 other patients showed that recognition of the HCL cells by the BV2+ T cells was restricted by HLA-DQA1*03/DQB1*0301, and the BV8S3+ T cells were restricted by DPB1*04. The T-cell clones did not recognize DPB1*04+ or DQ3+ PBMC from healthy donors or DP/DQ matched malignant cells from patients with other hematologic malignancies, except for one patient with acute lymphoblastic leukemia. These HCL-specific T-cell clones may be used for the detection of an HCL-specific tumor antigen.

Hairy Cell Leukemia-Specific Recognition by Multiple Autologous HLA-DQ or DP-Restricted T-Cell Clones

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 251-259 ◽  
Author(s):  
Lisette van de Corput ◽  
Hanneke C. Kluin-Nelemans ◽  
Michel G.D. Kester ◽  
Roel Willemze ◽  
J.H. Frederik Falkenburg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hairy Cell Leukemia ◽  
Lymphoblastic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
T Cell Clones ◽  
Cell Clones ◽  
Hla Dq ◽  
T Cell Clone

Abstract We studied in patients with hairy cell leukemia (HCL) whether autoreactive T cells could be isolated with specific reactivity to the HCL cells. HCL cells were activated via triggering of CD40 on the cell membrane and used as stimulator cells to generate autologous T-cell clones. Two types of CD4+BV2+ T-cell clones with different CDR3 rearrangements and one type of CD4+BV8S3+ T-cell clone were generated from the spleen or blood. These clones specifically recognized the autologous HCL cells, without reactivity to autologous peripheral blood mononuclear cells (PBMC), phytohemagglutinin blasts, or Epstein-Barr virus–transformed B cells in a primed lymphocyte test. Blocking and panel studies using HCL cells from 11 other patients showed that recognition of the HCL cells by the BV2+ T cells was restricted by HLA-DQA1*03/DQB1*0301, and the BV8S3+ T cells were restricted by DPB1*04. The T-cell clones did not recognize DPB1*04+ or DQ3+ PBMC from healthy donors or DP/DQ matched malignant cells from patients with other hematologic malignancies, except for one patient with acute lymphoblastic leukemia. These HCL-specific T-cell clones may be used for the detection of an HCL-specific tumor antigen.

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

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4224-4231 ◽  
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.

Functional and Numerical T Cell Abnormalities in Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3085-3085
Author(s):  
Mark C. Lanasa ◽  
Marc C. Levesque ◽  
Sallie D. Allgood ◽  
Jon P. Gockerman ◽  
Karen Bond ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Unequal Variances

Abstract Background: Although most malignancies are associated with decreased numbers of circulating T cells, in CLL they are elevated 2 to 4 times normal. Rather than promoting an anti-tumor response, this increased population of T cells may contribute to a tumor microenvironment that fosters progression of the malignant clone. Immunocompetent individuals show a wide repertoire of antigen specificity in both CD4+ and CD8+ T cells, but the T cell repertoire is significantly restricted in CLL. This restriction of the T cell repertoire may be an important cause of infectious morbidity in patients with CLL. To better understand these T cell abnormalities, we enumerated T cell subsets and determined T cell receptor diversity in 18 untreated patients with CLL. Methods: T cell subsets were enumerated from peripheral blood using highly sensitive 6-color flow cytometry. The T cell repertoire was determined for 23 T cell receptor variable β chain families (TCRvβ) in purified CD4+ and CD8+ T cells. These T cell subsets were considered separately because differential restriction of the CD4+ and CD8+ subsets has been reported previously. A PCR-based spectratype assay was used to analyze the length distribution of the TCR complementarity-determining region 3 (CDR3). A limitation of prior reports using spectratype assays was that adequately complex statistical models did not exist to simultaneously analyze the highly diverse vβ families. We addressed this limitation by using a recently-developed statistical method for spectratype analysis (Bioinformatics. 21:3394–400). Briefly, for each vβ family, the divergence from an expected reference distribution was calculated. A divergence coefficient was determined for each vβ family, and the mean divergence of all 23 vβ families was calculated. This allowed for statistical comparisons among individual patients and specific vβ families. To our knowledge, we are the first group to apply this powerful methodology to the analysis of T cell repertoires in patients with CLL. Results: We found both the CD4+ and CD8+ subsets to be expanded (mean #/μL ± SD: 1134 ± 646 and 768 ± 716, respectively; reference normal CD4+ range 401–1532, CD8+ 152–838). The absolute number of CD4+ and CD8+ T cells was greater in patients with higher absolute CLL lymphocyte counts (p = 0.018, r2 = 0.30, and p = 0.23, r2 = 0.09, respectively, linear regression). The CD4:CD8 ratio was lower in IgVH unmutated subjects (mutated 2.6, umutated 1.7, p = 0.09, two-tailed t-test assuming unequal variances). Though prior reports have disagreed on whether CD4+ or CD8+ subsets show greater restriction of clonality, we observed striking clonal restriction of CD8+ but not CD4+ T cells (p < 1×10−7, 2 sided t-test assuming unequal variances). There was a trend toward greater restriction of the CD8+ subset among patients with IgVH unmutated and Zap70+ CLL, but there was no correlation with lymphocyte doubling time. Conclusions: In this cohort of 18 untreated patients with CLL, there was a greater proportional increase compared to reference standards of CD8+ versus CD4+ T cells. However, the increase in CD4+, but not CD8+, T cell numbers was significantly correlated to total CLL lymphocyte count. This observation suggests that expansion of the CD4+ T cell pool observed in CLL is proportional to leukemic burden. The restriction of TCRvβ was limited to CD8+ T cells and that this effect was independent of the size of the abnormal clone. Taken together, these findings suggest different mechanisms of dysregulation of CD4+ and CD8+ T cell subsets in CLL.

scholarly journals B-ly-7, a monoclonal antibody reactive with hairy cell leukemia, also defines an activation antigen on normal CD8+ T cells [see comments]

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 959-964
Author(s):  
SP Mulligan ◽  
P Travade ◽  
E Matutes ◽  
C Dearden ◽  
L Visser ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Hairy Cell Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Activation Antigen

We undertook a study to determine the specificity of the monoclonal antibody, B-ly-7, for hairy cell leukemia (HCL) by examining the expression in 150 samples from B-cell lymphoproliferative diseases as well as screening for reactivity in a number of other hematologic malignancies. Within the B-cell lineage we found that the expression of B-ly-7 was highly specific for HCL and reacted with all 28 cases examined, as well as with 3 of 9 cases of a variant form of HCL. Cells of other closely related B-cell disorders, prolymphocytic leukemia, and splenic lymphoma with villous lymphocytes were negative. Investigation of the peripheral blood and bone marrow of patients with HCL before and after treatment with alpha-interferon or deoxycoformycin suggests that B-ly-7 may be useful in the assessment of minimal disease after therapy. In addition to HCL, we found that B-ly-7 was positive with cells of three mature, CD4+ T-cell malignancies. In view of the reactivity with malignancies of activated B and T cells, we searched for the expression of B-ly-7 on activated, normal B and T cells and found that B-ly-7 reacted specifically with activated normal peripheral blood CD8+ T cells. B-ly-7 has a number of applications, including the precise classification of mature B-cell neoplasia and the diagnosis HCL and its assessment after treatment. In addition, B-ly-7 recognizes a small subset of T-cell disorders. Its expression on these malignancies and on in vitro activated peripheral blood CD8+ T cells suggests that B- ly-7 detects a lymphocyte activation antigen.

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