scholarly journals CD1d expression on chronic lymphocytic leukemia B cells affects disease progression and induces T cell skewing in CD8 positive and CD4CD8 double negative T cells

Oncotarget ◽  
2016 ◽  
Vol 7 (31) ◽  
pp. 49459-49469 ◽  
Author(s):  
Nadja Zaborsky ◽  
Franz Josef Gassner ◽  
Daniela Asslaber ◽  
Petra Reinthaler ◽  
Ursula Denk ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Lymphocytic Leukemia ◽  
Double Negative ◽  
Double Negative T Cells

scholarly journals Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Colado ◽  
Esteban Enrique Elías ◽  
Valeria Judith Sarapura Martínez ◽  
Gregorio Cordini ◽  
Pablo Morande ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Immunomodulatory Effects ◽  
Immunoglobulin Preparations

AbstractHypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

CD4+ T-Cell Converted Double Negative T-Cells Suppress B-Cells Proliferation and IGG Production in Mice.

2014 ◽  
Vol 98 ◽  
pp. 391
Author(s):  
W. Li ◽  
X. Zhao ◽  
Y. Tian ◽  
W. Shi ◽  
X. Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cd4 T Cell ◽  
Double Negative ◽  
Double Negative T Cells

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.

Defective T Cell Migration in Chronic Lymphocytic Leukemia Is Repaired by Lenalidomide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3117-3117
Author(s):  
Alan G. Ramsay ◽  
Lena Svensson ◽  
Nancy Hogg ◽  
John G. Gribben
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Direct Contact ◽  
Immune Surveillance ◽  
Lymphocytic Leukemia ◽  
T Cell Migration

Abstract We have previously demonstrated that multiple gene expression abnormalities are induced in T cells from chronic lymphocytic leukemia (CLL) patients including defects within the actin cytoskeleton signaling pathways that control immune recognition and motility (Gullu et al. JCI, 2005). T cell immune surveillance requires rapid migratory responses and LFA-1 (CD11a/CD18; αLβ2) is a promigratory receptor that engages the cytoskeleton to control migration. We hypothesized that CLL T cells may exhibit dysfunctional migration in response to ICAM-1, the principal ligand for LFA-1. Using time lapse microscopy, we observed significantly reduced chemokine SDF-1 (CXCL12) induced migration on ICAM-1 of CLL CD4 and CD8 T cells compared to age-matched healthy donor T cells. Healthy T cells tracked for 45 min displayed a random course of migration with an average speed of ~ 8 μm/min, whereas CLL T cells were slower ~ 5 μm/min (n=14, ~ 30% reduction, p<0.01). We further postulated that direct contact of CLL tumor cells with healthy T cells would induce this migratory defect. Healthy CD4 or CD8 T cells were cocultured with either allogeneic CLL B cells or allogeneic healthy B cells and subsequently used in migration assays. Co-culture with CLL cells resulted in significantly reduced T cell migration compared with co-culture with healthy B cells (~ 44% reduction in migration, n=6, p<0.01). Evidence that direct contact was required to induce this migratory defect was shown when no effect was observed when cell-cell adhesion was prevented by pretreatment of CLL cells with anti-ICAM-1 blocking antibody prior to primary co-culture with healthy T cells. This cancer-induced migratory defect was repaired when CLL T cells were pretreated with the immunomodulatory drug Lenalidomide (1μM for 1hr). Treatment with this agent enhanced the migratory potential of CLL T cells to a speed comparable to untreated and treated healthy T cells. The finding that lenalidomide can restore rapid migration in patient T cells provides evidence that this agent may increase immune surveillance in 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.

scholarly journals A Detailed Analysis of Parameters Supporting the Engraftment and Growth of Chronic Lymphocytic Leukemia Cells in Immune-Deficient Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Piers E. M. Patten ◽  
Gerardo Ferrer ◽  
Shih-Shih Chen ◽  
Jonathan E. Kolitz ◽  
Kanti R. Rai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Intraperitoneal Administration ◽  
Human Condition ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Quiescent State

Patient-derived xenograft models of chronic lymphocytic leukemia (CLL) can be created using highly immunodeficient animals, allowing analysis of primary tumor cells in an in vivo setting. However, unlike many other tumors, CLL B lymphocytes do not reproducibly grow in xenografts without manipulation, proliferating only when there is concomitant expansion of T cells. Here we show that in vitro pre-activation of CLL-derived T lymphocytes allows for a reliable and robust system for primary CLL cell growth within a fully autologous system that uses small numbers of cells and does not require pre-conditioning. In this system, growth of normal T and leukemic B cells follows four distinct temporal phases, each with characteristic blood and tissue findings. Phase 1 constitutes a period during which resting CLL B cells predominate, with cells aggregating at perivascular areas most often in the spleen. In Phase 2, T cells expand and provide T-cell help to promote B-cell division and expansion. Growth of CLL B and T cells persists in Phase 3, although some leukemic B cells undergo differentiation to more mature B-lineage cells (plasmablasts and plasma cells). By Phase 4, CLL B cells are for the most part lost with only T cells remaining. The required B-T cell interactions are not dependent on other human hematopoietic cells nor on murine macrophages or follicular dendritic cells, which appear to be relatively excluded from the perivascular lymphoid aggregates. Notably, the growth kinetics and degree of anatomic localization of CLL B and T cells is significantly influenced by intravenous versus intraperitoneal administration. Importantly, B cells delivered intraperitoneally either remain within the peritoneal cavity in a quiescent state, despite the presence of dividing T cells, or migrate to lymphoid tissues where they actively divide; this dichotomy mimics the human condition in that cells in primary lymphoid tissues and the blood are predominately resting, whereas those in secondary lymphoid tissues proliferate. Finally, the utility of this approach is illustrated by documenting the effects of a bispecific antibody reactive with B and T cells. Collectively, this model represents a powerful tool to evaluate CLL biology and novel therapeutics in vivo.

scholarly journals Lysis of malignant B cells from patients with B-chronic lymphocytic leukemia by autologous T cells activated with CD3 x CD19 bispecific antibodies in combination with bivalent CD28 antibodies

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1803-1812 ◽  
Author(s):  
H Bohlen ◽  
T Hopff ◽  
O Manzke ◽  
A Engert ◽  
D Kube ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Bispecific Antibodies ◽  
Autologous Tumor ◽  
Activation Markers

Abstract Bispecific antibodies (bi-MABs) can be used to target T cells to autologous tumor cells. It has been shown that the activation of resting human T cells requires two independent signals, namely the cross-linking of the T-cell receptor (TCR)-CD3 complex together with the CD28 homodimer. In the present study, we demonstrate the activation of T cells from patients with chronic lymphocytic leukemia (CLL) using bi-MABs against the CD3 and CD19 antigens (CD3 x CD19) in combination with monospecific, bivalent antibodies against the CD28 antigen. Mononuclear cells from patients with CLL were cultured with the bi-MAB CD3 x CD19 and monospecific CD28 antibodies. The CD3 x CD19 bi-MABs were isolated by the hybridoma-hybridoma fusion technique and purified by hydrophobic interaction chromatography. T-Cell activation as demonstrated by increased proliferation, upregulation of T-cell activation markers (CD25, CD38), and cytotoxicity against autologous CLL cells and allogeneic B cells was shown in seven of eight CLL specimens. The stimulation with CD3 x CD19 bi-MABs with CD28 antibodies preferentially induced proliferation of CD4+ T cells. The effective dose of purified antibodies required for optimal T-cell activation was 100 ng/mL in vitro, which suggests that this antibody combination may be useful for immunotherapy of patients with B-CLL.

Significantly Shorter Telomeres in T-Cells of ZAP-70+/CD38+ Patients with Chronic Lymphocytic Leukemia (CLL): An Important Role of T-Cells in This Subgroup of CLL?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1120-1120
Author(s):  
Alexander Roeth ◽  
Dirk de Beer ◽  
Holger Nueckel ◽  
Ludger Sellmann ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Memory T Cells ◽  
Lymphocytic Leukemia ◽  
Healthy Individuals ◽  
Cell Numbers

Abstract BACKGROUND: In contrast to other B-cell neoplasias, chronic lymphocytic leukemia (CLL) is not only characterized by a clonal expansion of specific B-cells, but also by an increase in non-leukemic T-cells, most likely involved in sustaining the growth of the leukemic B-cell clone. Based on ZAP-70, CD38 and the IgVH mutation status, two prognostic groups of CLL patients can be identified. Our aim was to characterize the replicative histories of the B- and T-cells in the two groups of CLL patients compared to healthy individuals. PATIENTS and METHODS: Blood samples from 73 patients with CLL (ZAP-70−/CD38−: n = 29, ZAP-70+/CD38+: n = 30, ZAP-70/CD38 discordant: n = 14) were analyzed. The quantity and characteristics of the lymphocyte subsets was assessed by a cell counter and by immunophenotypic analysis. The replicative histories of naive and memory T-cells as well as B-cells was determined by measurements of telomere length in peripheral blood leukocytes of CLL patients and healthy individuals by automated multicolor flow-FISH. RESULTS: As expected, the average telomere length of the clonal B-cells was short. The telomere length was, however, significantly shorter for the ZAP-70+/CD38+ patient samples (2.46 ± 1.08 kb) than for the ZAP-70−/CD38− patient samples (5.06 ± 1.76 kb, p < 6.7 x 10−9). Interestingly, also the naive and memory T-cells from ZAP-70+/CD38+ CLL patients exhibited significantly shorter average telomere lengths (mean ± std: 4.85 ± 1.58 kb; 4.39 ± 1.09 kb) than T-cells from ZAP-70−/CD38− CLL patients (6.64 ± 1.72 kb, p < 2.2 x 10−4; 6.22 ± 1.5 kb, p < 7.4 x 10−6). These results are in line with the observed higher absolute T-cell numbers in the ZAP-70+/CD38+ CLL patients compared to ZAP-70−/CD38− CLL patients. Moreover, the average telomere loss in relation to time from primary diagnosis to sample date was higher for naive T-cells than memory T-cells in ZAP-70+/CD38+ patients (7.8 vs. 5.8 bp/month). When we compared the telomere length to age-related percentiles calculated from over 400 healthy individuals aged 0–102 years practically all telomere length values of the naive and memory T-cells from the ZAP-70+/CD38+ CLL patients fell below the 50th percentile, whereas the values of naive and memory T-cells from the ZAP-70−/CD38− CLL patients were within the normal distribution. CONCLUSIONS: We can confirm significantly shorter telomere length values for the B-cells of the ZAP-70+/CD38+ CLL patients. In addition, we can also demonstrate significantly shorter telomeres in T-cells of ZAP-70+/CD38+ CLL patients, which are below the 50th percentile compared to controls, and a higher telomere loss over time for naive T-cells of ZAP-70+/CD38+ CLL patients. As telomere length shortens approximately 50 to 100 bp per cell division the observed decrease in telomere length of the T-cells in ZAP-70+/CD38+ CLL patients equals to approximately 18 to 36 population doublings. This is by far more than expected by the slightly higher T-cell numbers in the peripheral blood. Our observations imply an extensive expansion of the T-cell compartment in ZAP-70+/CD38+ CLL patients and suggest an important role of T-cells in this subgroup of CLL patients.

Downregulation of IL-17-producing T cells is associated with regulatory T cell expansion and disease progression in chronic lymphocytic leukemia

Tumor Biology ◽  
2012 ◽  
Vol 34 (2) ◽  
pp. 929-940 ◽  
Author(s):  
Farhad Jadidi-Niaragh ◽  
Ghasem Ghalamfarsa ◽  
Ali Memarian ◽  
Hossein Asgarian-Omran ◽  
Seyed Mohsen Razavi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Regulatory T Cell ◽  
Cell Expansion ◽  
Lymphocytic Leukemia ◽  
T Cell Expansion

Clinical Significance of Free Circulating CD3 and CD5 in Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4947-4947
Author(s):  
Menna Hodge ◽  
Susan O’Brien ◽  
Adam Abdool ◽  
Michael Keating ◽  
Iman Jilani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Normal Control ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Β2 Microglobulin ◽  
Control Subjects

Abstract &lt;/DEL&gt; CD5, a transmembrane protein expressed in T-cells, few B-cells, and chronic lymphocytic leukemia (CLL) B-cells, is the ligand for CD72 and may play a role in B-cell-T-cell communication. CD5 is part of the T-cell receptor (TCR)-CD3 complex in T-cells as well as the B-cell receptor (BCR) complex and serves as substrate for induction of tyrosine kinase activity. Since leukemic cells have high turnover and pour their protein, RNA, and DNA into the circulation, we speculated that free circulating CD3 (cCD3) and CD5 (cCD5) could be detected in the plasma of patients with CLL. We have developed a bead-based sandwich immunoassay to measure cCD3 and cCD5 in the plasma. Using this assay, we assessed the value of cCD5 measurement, alone and after normalization to cCD3 levels, as a tumor marker in CLL. Plasma levels of cCD3 and cCD5 were measured in 85 patients with CLL and 51 normal control subjects. cCD3 and cCD5 levels were significantly higher in patients with CLL (median, 7,465 and 55,806 U/μl, respectively) than in normal control subjects (median, 830 and 1,671 U/μl, respectively). Patients with CLL had significantly higher cCD5:cCD3 ratios (median, 5.28; range, 0–161) than did normal controls (median, 1.70; range, 0–8.06) (P &lt;0.0001). Levels of cCD5, but not cCD3, correlated positively with WBC count, β2-microglobulin level, splenomegaly, and Rai stage (all P &lt;0.01). The cCD5:cCD3 ratio also correlated with Rai stage (P = 0.04) and β2-microglobulin level (P = 0.03). cCD5 levels and the cCD5:cCD3 ratio both correlated with survival (P = 0.03). These findings confirm that free circulating surface markers can be detected in the circulation of patients with CLL, most likely reflect the tumor load, and can be used as tumor markers. The biological and therapeutic relevance of these free circulating proteins should be considered in pharmacokinetic and pharmacodynamic studies.

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