CTLA-4 overexpression in CD19+/CD5+ cells correlates with the level of cell cycle regulators and disease progression in B-CLL patients.
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Antigens, CD↗
Biomedical subjects
I Frydecka
Publications and source records attributed to I Frydecka.
Alterations of the expression of T-cell-related costimulatory CD28 and downregulatory CD152 (CTLA-4) molecules in patients with B-cell chronic lymphocytic leukaemia.
In the present study, we have examined the kinetics and magnitude of expression of the CD28 and CD152 molecules on unstimulated and anti-CD3+rIL-2-stimulated peripheral blood CD4+ and CD8+ T cells in patients with chronic lymphocytic leukaemia (B-CLL) and controls. The mean percentages of both CD3+/CD4+/CD28+ and CD3+/CD8+/CD28+ cells were significantly lower in B-CLL than in controls before culture, decreased rapidly, reaching their lowest levels between 24 and 48 h, and returned to basal levels after 72 h of culture. In controls, the lowest proportions of CD3+/CD4+/CD28+ and CD3+/CD8+/CD28+ cells were found after 24 h and returned to prestimulation levels after 48 h of stimulation. We observed significantly higher proportions of unstimulated CD3+/CD4+/CD152+ and CD3+/CD8+/CD152+ cells in B-CLL patients than in controls. The highest percentages of CD3+/CD4+/CD152+ and CD3+/CD8+/CD152+ cells were observed in controls after 72 h, and in B-CLL patients after 24 h, and remained statistically higher after 48, 72 and 96 h of stimulation. CD152 molecule expression returned to prestimulation levels after 96 h of culture in controls, and after 120 h in B-CLL patients. The abnormal kinetics and levels of CD28 and CD152 expression on T cells in B-CLL may lead to a state of hyporesponsiveness or anergy and could be one of the mechanisms of immune deficiency in this disease.
Adult↗
Progression of multiple sclerosis is associated with exon 1 CTLA-4 gene polymorphism.
OBJECTIVES: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system which is widely believed to have a T-cell-mediated etiology. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) antigen molecule plays a key role in the downregulation of T-cell responses. To examine the genetic association of the CTLA-4 gene locus with MS, we analyzed an exon 1 (A49G) transition. MATERIAL AND METHODS: One hundred and fifty-two MS patients and 154 controls were examined. The A/G transition was genotyped by a polymerase chain reaction followed by labeling with a SNaPshot kit and detection using a capillary genetic analyzer. RESULTS: The genotype, allele and phenotype frequencies did not differ significantly between MS patients and controls. Those MS patients with AA and AG genotypes had 4.36 times greater risk of progressing from the relapsing-remitting to the secondary progressive form of the disease than those with the GG genotype. CONCLUSION: The results of our study indicate that CTLA-4 (A49G) exon 1 polymorphism is associated with MS progression.
Adult↗
Fas expression on T cells and sFas in relapsing-remitting multiple sclerosis.
OBJECTIVES: To investigate the proportions of peripheral blood CD4+/Fas+ and CD8+/Fas+ cells and serum sFas levels in relapsing-remitting multiple sclerosis (RRMS) patients with relapses (active RRMS), those without relapses (stable RRMS), and controls over 1 year. MATERIAL AND METHODS: Sixteen RRMS patients and 10 controls were tested monthly. Cells were analyzed by dual immunofluorescence and the sFas levels by ELISA. There were 14 relapses which occurred 1223 days after the last control visits. The measurements performed at these visits in the active RRMS patients were considered as relapse-related, while the rest were regarded as relapse-unrelated. RESULTS: In active RRMS patients the median of CD4+ Fas+ to total CD4+ and CD8+ Fas+ to total CD8+ from relapse-related measurements were higher than the median from relapse-unrelated measurements (P=0.003, 0.004, respectively). The median of CD4+ Fas+ to total CD4+ from relapse-unrelated measurements in active RRMS was higher compared with stable RRMS (P = 0.005) and controls (P = 0.004). The sFas level from relapse-unrelated measurements was also higher in active RRMS than in stable RRMS (P = 0.04) and in controls (P = 0.004). CONCLUSIONS: We suggest that increased expression of Fas antigen on CD4+ subset and increased serum sFas level are valuable markers of clinical activity in MS.
Adult↗
The effect of peripheral blood lymphocyte stimulation on zeta chain expression and IL-2 production in Hodgkin's disease.
It has been reported that peripheral blood T cells and NK cells express reduced levels of the T-cell receptor signal-transducing zeta chain in Hodgkin's disease (HD). The zeta chain has emerged as a key subunit of the T-cell antigen receptor, which plays a central role in the signal-transducing events leading to T and NK-cell activation. We were interested in determining whether the low zeta chain expression in HD could be corrected by anti-CD3, anti-CD3-rIL-2 ex vivo stimulation. Zeta chain expression was analysed by dual immunofluorescence on permeabilized cells before and after 72 hours of culture. The IL-2 concentration in the culture supernatants was measured by ELISA. Zeta chain was significantly reduced on unstimulated CD4+, CD8+ and CD56+ cells from patients in active disease compared with normal subjects. In patients in complete remission, the values were normal except for CD8+ cells, on which zeta expression remained significantly reduced. Stimulation with anti-CD3 did not change zeta expression. Co-stimulation with rIL-2 increased but did not normalize the proportions of CD4(+)/zeta(+), CD8(+)/zeta(+)and CD56(+)/zeta(+)cells and IL-2 production in active disease. Stimulation of cells from patients in clinical remission with anti-CD3(+)rIL-2 increased the proportion of CD8(+)zeta(+)cells and normalized IL-2 production levels. Considering the pivotal role of CD3-zeta in immune response, our data suggest that successful immunotherapy approaches in active HD should consider inclusion of other potent cytokines, as well as genetically engineered tumour vaccines.
Adult↗
Expression and functional significance of CTLA-4, a negative regulator of T cell activation.
The generation of an effective immune response involves antigen-specific T cell expansion and differentiation of effector function. T cell activation requires at least two distinct signals, including signaling via the antigen-specific T cell receptor (TCR) and a costimulatory pathway. Antigen stimulation of T cells can lead either to a productive immune response, characterized by proliferation, differentiation, clonal expansion and effector function, or, in the absence of an appropriate costimulation, to a state of long-lasting unresponsiveness, termed anergy. Anergic T cells fail to proliferate and secrete cytokines in response to secondary stimulation. The interaction between the costimulatory molecule CD28 on T cells and members of the B7 family on antigen-presenting cell results in upregulation of T cell proliferation and cytokine production and induces the expression of the anti-apoptotic protein Bcl-xl. Based of these findings, the two-signal requirement model for T cell activation is generally accepted today. The negative regulatory mechanisms during T cell activation are not well understood, but they are crucial for the maintainance of lymphocyte homeostasis. For several years the functional role of the enigmatic CD28 homologue cytotoxic T lymphocyte antigen-4 (CTLA-4) in T cell activation has been both obscure and controversial. CTLA-4 was initially supposed to provide a costimulatory signal in conjunction with TCR/CD3 signaling. Today we know that CD28 and CTLA-4 molecules may have diametrically opposed functions: signaling via CD28, in conjunctive with TCR, is required for T cell activation, while signaling via CTLA-4 is a negative signal that inhibits T cell proliferation. How the T cell integrates signals through the TCR/CD3 complex, CD28 and CTLA-4 to initiate, maintain and terminate antigen-specific immune response is in fact not fully clarified. In this review, we will focus on the emerging role of CTLA-4 as a negative regulator of T lymphocyte activation and its role in the dynamic interplay of activatory and inhibitory signals.
Abatacept↗
Cell cycle regulatory proteins and apoptosis in B-cell chronic lymphocytic leukemia.
BACKGROUND AND OBJECTIVES: The pathogeny of B-cell chronic lymphocytic leukemia (B-CLL) involves both deregulated proliferation and inhibition of cell death. A particular role in the regulation of these phenomena is played by proteins involved in early G1 phase regulation: pRb kinases: cyclin-dependent kinases (cdk): cdk4 and cdk6 activated by cyclins D, and universal cdk inhibitor p27(Kip1). DESIGN AND METHODS: We determined by flow cytometry the expression of p27(Kip1) and cyclins D (D2 and D3) in populations of peripheral blood lymphocytes obtained from 59 (for p27(Kip1)) and 31 (for cyclins D) previously untreated patients with B-CLL, and compared them with cell cycle parameters, cell viability and apoptosis in 72-hour cultures in medium only. As a control we determined the expression of p27(Kip1), cyclin D2 and D3 in peripheral blood CD5+/CD19+ lymphocytes from 15 healthy donors. RESULTS: p27(Kip1) was present in nearly 100% of lymphocytes in all B-CLL populations tested. Its cellular content estimated semiquantitatively by specific mean fluorescence intensity was higher than in normal CD5+/CD19+ lymphocytes, p27(Kip1) was inversely correlated with patients' age and not correlated with other clinical variables, cell cycle or apoptosis rate. Cyclin D2 was detectable in 25 out of 31, and cyclin D3 in all B-CLL lymphocytes populations studied. In contrast to p27Kip1 present in all CD5+/CD19+ lymphocytes, both cyclins were detected only in a subset of neoplastic cells: 27.5 to 87% (mean 51.2) for cyclin D2 and 20.3 to 98% (mean 76.5) for cyclin D3. In cyclin D2- and D3-positive normal CD5+/CD19+ lymphocytes and B-CLL cell populations, cyclin D3 was expressed in a higher percentage of cells than cyclin D2. Both cyclin D2-and cyclin D3-positive fractions of B-CLL cells were, on average, larger than corresponding fractions of normal CD5+/CD19+ peripheral blood lymphocytes. INTERPRETATION AND CONCLUSIONS: Our results indicate that cyclin D3 plays an important role in the regulation of normal and neoplastic CD5+/CD19+ cells, and point to the possibility of the exit of a number of CLL lymphocytes from quiescence.
Adult↗
Expression of signal-transducing zeta chain in peripheral blood T cells and natural killer cells in patients with Hodgkin's disease in different phases of the disease.
A number of phenotypic and functional alterations have been described in T cells of cancer patients. These changes are believed to reflect an impaired T-cell mediated immunity, which in turn, may result in a decreased capacity to generate an effective antitumor response. Several mechanisms have been proposed to explain depressed immunity in cancer patients including tumor-derived suppressor factors, abnormal cytokine production, deletion or inactivation of tumor-reactive T-cells. To investigate the mechanism underlying the immunodeficiency in Hodgkin's disease (HD) we studied the expression of T cell receptor zeta chain, which plays a vital role in the cascade of events leading to T and NK cell activation. The expression of the zeta chain of the T cell receptor/CD3 complex was analyzed by dual colour immunofluorescence on peripheral blood T lymphocytes: CD3+, CD4+, CD8+ and NK-cells (CD56+) in patients in different phases of the disease. Zeta chain was significantly reduced on CD3, CD4, CD8, and CD56 positive cells from patients in active phase of the disease compared with normal controls (p=0.05). In patients tested in complete clinical remission the values were normal except for the subpopulation of CD8+ cells in which the expression of zeta chain remained significantly reduced compared with controls. Downregulation of CD3/zeta-chain in PBLs and NK cells in active phase of HD- and to a lesser extent in clinical remission may contribute to immunodeficiency associated with the disease.
Adult↗
[The level of soluble forms of interleukin-2 receptor and adhesive molecules ICAM-1 and VCAM-1 in platelets of multiple sclerosis patients].
The levels of sIL-2R alpha, sICAM-1, and sVCAM-1 in sera of patients with clinically probable multiple sclerosis (ms) during the first relapse were assessed. In ms patients the levels of these 3 soluble molecules were significantly increased in comparison with the results obtained in controls. The results reflected activation of lymphocytes T and enhancement expression of adhesion molecules on brain endothelial cells, therefore they could serve indirectly as markers of immunological activation in multiple sclerosis. Any of the levels of soluble molecules in sera did not correlate with the severity of the disease.
Adult↗
Immunotherapy with recombinant human interleukin 2 in patients with hematological malignancies after bone marrow or peripheral blood stem cell transplantation.
High-dose chemotherapy in conjunction with bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) is increasingly being used for treatment of patients with hematological malignancies. Residual tumor cells, resistant to high-dose chemoradiotherapy, are responsible for reccurence of the disease. Interleukin 2 (IL-2), a pleiotropic cytokine which plays a central role in immune response, has been introduced in several clinical trials in patients with hematological malignancies after BMT or PBSCT to increase immunocompetence of these patients and eradicate residual malignant cells. At present there is no general agreement on the optimum dosage or route of administration and clinical trials also gave conflicting results. Establishment of optimum dosage schedules and methods of administration should enable a better assessment of the place of IL-2 in the treatment of these patients.
Bone Marrow Transplantation↗
Alterations in signal transducing molecule CD3 zeta in patients with neoplastic diseases.
The impairment of immune cell functions in cancer patients may result from impairment of signal transduction. Recent studies have demonstrated altered expression and function of signal transduction molecule CD3 zeta in T and natural killer cells in patients with neoplastic diseases. Tumor infiltrating lymphocytes are more affected than peripheral blood lymphocytes. CD3 zeta expression is more prominent in advanced stage of the disease and correlates with reduced proliferative response, IFN-gamma, IL-2, TNF-alpha production.
CD3 Complex↗
Serum soluble interleukin 2 receptor alpha and soluble CD8 levels in patients with gynecological malignancies undergoing radiotherapy.
The phenotype peripheral blood lymphocytes, soluble interleukin 2 receptor alpha (sIL-2R alpha) and soluble CD8 (sCD8) were studied in 30 patients with gynecological malignancies before and after ratiotherapy. The absolute count of CD3+, CD4+, CD8+, CD19+ and CD25+ lymphocytes before treatment was within normal range. The levels of serum sIL-2R alpha and sCD8 were significantly increased before treatment compared to normal controls. After treatment the absolute number of CD3+, CD4+ and CD19+ lymphocyte subsets significantly decreased. The levels of sIL-2 alpha and sCD8 corrected according to absolute lymphocyte count reached normal range. The decrease of tumor mass correlated with the serum levels of sIL-2R alpha and sCD8. Further studies are needed to evaluate the usefulness of these tests in the prognosis and treatment of these diseases. Our study suggests that sIL-2R alpha and sCD8 in our patients probably has not been originating from the proteolytic cleavage of membrane bound receptors from peripheral blood mononuclear cells (PBMC). It can be speculated that sIL-2R alpha and sCD8 originated in these patients from activated tumor-infiltrating lymphocytes or may arise from separate alternatively spliced mRNAs coding for soluble vs. membrane forms.
Adult↗
Impaired CD25 expression and soluble CD25-IL-2R alpha receptor release by anti-CD3 stimulated peripheral blood mononuclear cells in Hodgkin's disease patients.
We examined 22 patients in active phase of Hodgkin's disease (HD), 12 patients in complete clinical remission and 16 healthy subjects for their responsiveness to anti-CD3 stimulation as measured by CD25 antigen expression on peripheral blood mononuclear cells (PBMC) and production of CD25-IL-2R alpha. Simultaneously, the serum levels of soluble interleukin 2 receptor alpha (sIL-2R alpha) were estimated. Our studies indicate that PBMC in patients in active phase and in clinical remission have impaired ability to express CD25 antigen after stimulation with anti-CD3 monoclonal antibody. Similarly, the levels of sIL-2R alpha in culture supernatants were significantly lower in both groups of patients: in active phase and clinical remission compared with the controls. In contrast, the mean serum level of sIL-2R alpha was significantly higher in active phase of the disease compared to that found in patients in clinical remission and controls. Our studies suggest that sIL-2R alpha, derived from PBMC, is not the source of increased levels of sIL-2R alpha found in the sera of patients in active phase of HD. Their synthesis and secretion/shedding most probably takes place in the involved tissues.
Adolescent↗
Decreased production of interferon gamma by anti-CD3 monoclonal antibody and interleukin-2-stimulated peripheral blood mononuclear cells in Hodgkin's disease.
We have examined the production of interferon (IFN) gamma by peripheral blood mononuclear cells (PBMC) in 22 patients with Hodgkin's disease (HD) in active phase of the disease, 12 patients in clinical remission and 16 healthy subjects. The level of IFN gamma in supernatants of PBMC stimulated for 72 h with anti-CD3 monoclonal antibody (mAb), measured by sandwich enzyme immunoassay (ELISA) was 50.4 +/- 2.3 U/ml in active phase; 137.0 +/- 7.4 U/ml in clinical remission patients; and 520.0 +/- 10.0 U/ml in the controls; the difference between the groups was statistically significant. Co-stimulation with interleukin-2 (rIL-2) markedly amplified production of IFN gamma. The mean levels were 220.8 +/- 7.0 U/ml, 590.7 +/- 3.6 U/ml and 2111.1 +/- 17.3 U/ml in active phase HD, clinical remission and controls, respectively, the difference between groups was statistically significant. The patients showed the same kinetic pattern as healthy individuals. Our results indicate that patients with HD have severely impaired TCR/CD3 activation pathway resulting in significantly depressed IFN gamma response to anti-CD3 mAb and anti-CD3 + rIL-2 in vitro stimulation and provide support for the possible clinical use of IFN gamma as an immunopotentiating agent in patients with HD.
Adult↗
[Circulating cell differentiation antigens as markers of activity in lymphoproliferative diseases].
The presence of soluble differentiation antigens has been recently shown in the sera of healthy subjects and in different pathological disorders. These soluble antigens represent truncated froms of membrane receptors that lack transmembrane and intracytoplasmic domains. They may rise from proteolytic cleavage of the original membrane-bound receptor or by synthesis from separate alternatively spliced mRNA's coding for soluble forms. Increased levels of soluble IL-2R, sCD8 were found in adult T cell leukemia, hairy cell leukemia Hodgkin's disease, non-Hodgkin's lymphoma and chronic lymphocytic leukemia. The presence of sCD30 was found in the above mentioned diseases except for hairy cell leukemia. Serum levels of sIL-2R, sCD8, sCD30 antigens correlated strictly with disease activity and results of treatment.
Antigens, Differentiation↗
[Interleukin 2 (IL-2) and its receptor (IL-2R) in healthy individuals and with various disease states].
IL-2 is a cytokine that plays a central role in immune response. It stimulates cellular as well as humoral reactivity. The effect of IL-2 depends on the interaction with its receptor. Recent reports have documented that high affinity interleukin-2 receptors consist of two distinct IL-2 binding proteins, one being alpha chain (p55) and the other being IL-2 beta chain (p75). Expression of the alpha chain or the beta chain alone allows for low affinity or intermediate affinity IL-2 binding, respectively. Alpha receptor is present on activated cells, beta chain is present on resting cells. Decreased production of IL-2 and decreased expression of IL-2 receptor (IL-2R) after stimulation was found in primary and secondary immune deficiencies. Leukemic cells in adult T cell leukemia and hairy cell leukemia express markedly large numbers of IL-2 receptors. Since IL-2 receptors are present on malignant cells but not on normal resting cells, clinical trials have been initiated in which patients with adult T cell leukemia are treated with monoclonal antibody that binds to IL-2 receptor.
Antibodies, Monoclonal↗
Unusual case of granular lymphocytes (GL) proliferation: simultaneous reactive and neoplastic proliferation.
We report a case of a 55-year-old male with lymphoproliferative disease of granular lymphocytes. In the first year of follow-up reactive expansion of granular lymphocytes was observed during infectious episodes additionally to malignant proliferation. Histopathological studies revealed malignant lymphocytic infiltrations of the liver and gallbladder walls. The number of GL varied from 1.1 G/l to 17.8 G/l. Immunophenotyping studies showed surface phenotype CD3+, CD8+. There was markedly reduced NK cell function. The patient exhibited lack of severe parenchymal involvement, moderately increased white cell count (up to 21.0 G/l), severe neutropenia (0.06 G/l - 0.8 G/l) and recurrent infectious episodes.
Azure Stains↗
The lymphoproliferative disease of large granular lymphocytes.
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Cytoplasmic Granules↗