scholarly journals Molecular analysis of T-cell receptor V beta chains of human T-cell chronic lymphocytic leukemia does not show intraclonal variability: implications for immunotherapy

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2152-2156 ◽  
Author(s):  
F Picard ◽  
T Martin ◽  
F Legras ◽  
B Lioure ◽  
JL Pasquali
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Variable Regions ◽  
Human T Cell ◽  
Specific Antigens ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Human T-cell chronic lymphocytic leukemia (T-cell CLL) is a heterogeneous disease characterized by a monoclonal malignant proliferation of T cells in which the T-cell receptors (TCRs) can be, when expressed, considered to be membrane tumor-specific antigens. Owing to the increasing number of available monoclonal antihuman TCR reagents, it could be of interest to evaluate the feasibility of anti- TCR treatment during T-cell CLL. To test the therapeutic potentiality of anti-TCR monoclonal antibodies, we first analyzed the intraclonal variability in two terminally ill patients suffering from TCR alpha beta-positive cell CLL bearing different immunophenotypes. The cDNA corresponding to the variable regions of the TCR beta chains originating from the malignant T cells were amplified, cloned into M13 phages, and sequenced. The sequence analysis of multiple independent clones showed no intraclonal variability, with no evidence for ongoing hypermutation in the V beta region genes. The relevance of these findings with regard to an anti-V beta therapy and the comparison with similar analysis during B-cell monoclonal lymphoproliferations are discussed.

scholarly journals Molecular analysis of T-cell receptor V beta chains of human T-cell chronic lymphocytic leukemia does not show intraclonal variability: implications for immunotherapy

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2152-2156
Author(s):  
F Picard ◽  
T Martin ◽  
F Legras ◽  
B Lioure ◽  
JL Pasquali
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Variable Regions ◽  
Human T Cell ◽  
Specific Antigens ◽  
Cell Chronic Lymphocytic Leukemia

Human T-cell chronic lymphocytic leukemia (T-cell CLL) is a heterogeneous disease characterized by a monoclonal malignant proliferation of T cells in which the T-cell receptors (TCRs) can be, when expressed, considered to be membrane tumor-specific antigens. Owing to the increasing number of available monoclonal antihuman TCR reagents, it could be of interest to evaluate the feasibility of anti- TCR treatment during T-cell CLL. To test the therapeutic potentiality of anti-TCR monoclonal antibodies, we first analyzed the intraclonal variability in two terminally ill patients suffering from TCR alpha beta-positive cell CLL bearing different immunophenotypes. The cDNA corresponding to the variable regions of the TCR beta chains originating from the malignant T cells were amplified, cloned into M13 phages, and sequenced. The sequence analysis of multiple independent clones showed no intraclonal variability, with no evidence for ongoing hypermutation in the V beta region genes. The relevance of these findings with regard to an anti-V beta therapy and the comparison with similar analysis during B-cell monoclonal lymphoproliferations are discussed.

scholarly journals An antigen shared by a human T cell subset and B cell chronic lymphocytic leukemic cells. Distribution on normal and malignant lymphoid cells.

1980 ◽  
Vol 152 (1) ◽  
pp. 229-234 ◽  
Author(s):  
L Boumsell ◽  
H Coppin ◽  
D Pham ◽  
B Raynal ◽  
J Lemerle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Subset ◽  
Lymphocytic Leukemia ◽  
Lymphoid Cells ◽  
Antigenic Determinants ◽  
Human T Cell ◽  
Cell Chronic Lymphocytic Leukemia

We obtained a monoclonal antibody, A50, after immunizing Biozzi's high responder strain of mice with T cell chronic lymphocytic leukemia (T-CLL) cells. A50 recognized an antigen present on the surface of B cell chronic lymphocytic leukemia cells from many patients and from cells of T lineage from any subject we tested. We could not find this antigen either on the surface of normal B cell or on other non-T cell malignancies. On T cells, this antigen was present on a subpopulation of thymus cells, and on most peripheral T cells. The antigen was present on the surface of cells from T-CLL, Sézary's disease, and a subset o T cell lymphoma. The antigen seemed to belong to a complex set of antigenic determinants that we had defined with rabbit antisera.

scholarly journals Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1012-1020 ◽  
Author(s):  
JS Moore ◽  
MB Prystowsky ◽  
RG Hoover ◽  
EC Besa ◽  
PC Nowell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Specific Immunoglobulin ◽  
Cell Chronic Lymphocytic Leukemia

The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

CD40-Activated B-Cell Chronic Lymphocytic Leukemia Cells for Tumor Immunotherapy: Stimulation of Allogeneic Versus Autologous T Cells Generates Different Types of Effector Cells

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 1992-2002 ◽  
Author(s):  
Raymund Buhmann ◽  
Annette Nolte ◽  
Doreen Westhaus ◽  
Bertold Emmerich ◽  
Michael Hallek
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Tumor Antigens ◽  
Lymphocytic Leukemia ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Cell Chronic Lymphocytic Leukemia ◽  
Stimulation Of

Although spontaneous remissions may rarely occur in B-cell chronic lymphocytic leukemia (B-CLL), T cells do generally not develop a clinically significant response against B-CLL cells. Because this T-cell anergy against B-CLL cells may be caused by the inability of B-CLL cells to present tumor-antigens efficiently, we examined the possibility of upregulating critical costimulatory (B7-1 and B7-2) and adhesion molecules (ICAM-1 and LFA-3) on B-CLL cells to improve antigen presentation. The stimulation of B-CLL cells via CD40 by culture on CD40L expressing feeder cells induced a strong upregulation of costimulatory and adhesion molecules and turned the B-CLL cells into efficient antigen-presenting cells (APCs). CD40-activated B-CLL (CD40-CLL) cells stimulated the proliferation of both CD4+ and CD8+ T cells. Interestingly, stimulation of allogeneic versus autologous T cells resulted in the expansion of different effector populations. Allogeneic CD40-CLL cells allowed for the expansion of specific CD8+cytolytic T cells (CTL). In marked contrast, autologous CD40-CLL cells did not induce a relevant CTL response, but rather stimulated a CD4+, Th1-like T-cell population that expressed high levels of CD40L and released interferon-γ in response to stimulation by CD40-CLL cells. Together, these results support the view that CD40 activation of B-CLL cells might reverse T-cell anergy against the neoplastic cell clone, although the character of the immune response depends on the major histocompatibility complex (MHC) background on which the CLL or tumor antigens are presented. These findings may have important implications for the design of cellular immunotherapies for B-CLL.

Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2519-2519 ◽  
Author(s):  
Chia-Huey Lin ◽  
Thomas Kerkau ◽  
Christine Guntermann ◽  
Martin Trischler ◽  
Niklas Beyersdorf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Activation Markers ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B cell chronic lymphocytic leukemia (B-CLL) is characterised by an accumulation of malignant B cells, and impaired humoral and cellular immune responses. Evasion strategies of leukemic cells appear to involve down-regulation of co-stimulatory molecules as well as increased resistance to apoptosis. Here we provide data supporting a novel concept to treat B-CLL with a humanized, superagonistic monoclonal antibody specific for CD28 (TGN1412). Superagonistic anti-CD28 antibodies have been shown to activate human T cells in vitro without requirement for engagement of the T cell antigen receptor (Luhder et al., J. Exp. Med. 2003. 197(8):955–66). Indicative of their activation, TGN1412-triggered T cells from healthy donors upregulate, among other activation markers, CD40L, that has been reported to promote anti-leukemic effects when ectopically expressed on B-CLL cells (Wierda et al., Blood. 2000. 96 (9): 2917–2924). In this report, the responses of PBMCs from B-CLL patients to soluble TGN1412 were examined. We show that in a dose-dependent fashion, polyclonal T cell activation was induced by TGN1412 including proliferation, cytokine production and induction of activation markers such as CD25, CD71, CD134 (Ox40), CTLA-4 (CD152) and CD154 (CD40L). Significantly, modulation of malignant B-CLL cells was also observed. MHC class II molecules (HLA-DR), CD95 and the co-stimulatory molecules CD80 and CD86, but not the proliferation marker Ki-67, were strongly up-regulated upon TGN1412 stimulation. These data suggested that improved antigen-presenting functions of B-CLL cells were induced by TGN1412. Accordingly, preliminary data indicate that B-CLL cells isolated from TGN1412 stimulated cultures induced enhanced proliferation of both allogeneic and autologous T cells, and importantly, TGN1412 activated T cells exhibited enhanced CTL-activity against B-CLL cells. In conclusion, our data suggest that TGN1412 induces polyclonal T cell expansion and activation as well as increased APC function of B-CLL cells. They imply that TGN1412 may have future therapeutic benefit for B-CLL patients.

Leukemia-associated monoclonal and oligoclonal TCR-BV use in patients with B-cell chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 1063-1070 ◽  
Author(s):  
Mohammad-Reza Rezvany ◽  
Mahmood Jeddi-Tehrani ◽  
Hans Wigzell ◽  
Anders Österborg ◽  
Håkan Mellstedt
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cd8 T Cells ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

Abstract T-cell receptor–B-variable (TCR-BV) gene usage and the CDR3 size distribution pattern were analyzed by reverse transcription–polymerase chain reaction (RT-PCR) in patients with B-cell chronic lymphocytic leukemia (B-CLL) to assess the T-cell repertoire. The use of TCR-BV families in CD4 and CD8 T cells stimulated with autologous activated leukemic cells was compared with that of freshly obtained blood T cells. Overexpression of individual TCR-BV families was found in freshly isolated CD4 and CD8 T cells. Polyclonal, oligoclonal, and monoclonal TCR-CDR3 patterns were seen within such overexpressed native CD4 and CD8 TCR-BV families. In nonoverexpressed TCR-BV families, monoclonal and oligoclonal populations were noted only within the CD8 subset. After in vitro stimulation of T cells with autologous leukemic B cells, analyses of the CDR3 length patterns showed that in expanded TCR-BV populations, polyclonal patterns frequently shifted toward a monoclonal/oligoclonal profile, whereas largely monoclonal patterns in native overexpressed TCR-BV subsets remained monoclonal. Seventy-five percent of CD8 expansions found in freshly obtained CD8 T cells further expanded on in vitro stimulation with autologous leukemic B cells. This suggests a memory status of such cells. In contrast, the unusually high frequency of CD4 T-cell expansions found in freshly isolated peripheral blood cells did not correlate positively to in vitro stimulation as only 1 of 9 expansions continued to expand. Our data suggest that leukemia cell–specific memory CD4 and CD8 T cells are present in vivo of patients with CLL and that several leukemia cell–associated antigens/epitopes are recognized by the patients' immune system, indicating that whole leukemia cells might be of preference for vaccine development.

Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 1057-1063 ◽  
Author(s):  
Wendelina J. M. Mackus ◽  
Florine N. J. Frakking ◽  
Annette Grummels ◽  
Laila E. Gamadia ◽  
Godelieve J. de Bree ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Responses ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Lymphocytic Leukemia ◽  
The Absolute ◽  
Cell Chronic Lymphocytic Leukemia

Abstract In patients with B-cell chronic lymphocytic leukemia (B-CLL), the absolute number of T cells is increased. Although it has been suggested that these T cells might be tumor specific, concrete evidence for this hypothesis is lacking. We performed a detailed immunophenotypic analysis of the T-cell compartment in the peripheral blood of 28 patients with B-CLL (Rai 0, n = 12; Rai I-II, n = 10; Rai III-IV, n = 6) and 12 healthy age-matched controls and measured the ability of these patients to mount specific immune responses. In all Rai stages a significant increase in the absolute numbers of CD3+ cells was observed. Whereas the number of CD4+ cells was not different from controls, patients with B-CLL showed significantly increased relative and absolute numbers of CD8+ cells, which exhibited a CD45RA+CD27- cytotoxic phenotype. Analysis of specific immune responses with tetrameric cytomegalovirus (CMV)–peptide complexes showed that patients with B-CLL had significantly increased numbers of tetramer-binding CMV-specific CD8+ T cells. The rise in the total number of CD8+ cytotoxic T cells was evident only in CMV-seropositive B-CLL patients. Thus, our data suggest that in patients with B-CLL the composition of T cells is shifted toward a CD8+ cytotoxic cell type in an effort to control infections with persistent viruses such as CMV. Moreover, they offer an explanation for the high incidence of CMV reactivation in CLL patients treated with T cell–depleting agents, such as the monoclonal antibody (mAb) alemtuzumab (Campath; α-CD52 mAb). Furthermore, because in CMV-seronegative patients no increase in cytotoxic CD8+ T cells is found, our studies do not support the hypothesis that tumor-specific T cells account for T-cell expansion in B-CLL.

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