bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deregulated cytokine network and defective Th1 immune response in multiple myeloma
Authors: Frassanito M A , Cusmai A , Dammacco F 
Published: March 2003

SummaryIntracellular cytokine production by peripheral blood mononuclear cells (PBMC) was analysed in 51 patients with multiple myeloma (MM), 22 with monoclonal gammopathy of undetermined significance (MGUS) and 20 healthy subjects, as a parameter of immunological dysfunction in MM. An increased proportion of T cells and HLA-DR+ cells producing IL-6 was observed in MM patients with active disease (at diagnosis and relapsing) compared with patients in remission and with MGUS, whereas no difference of IFN-γ+, IL-2+ PBMC between patients and controls was evident. Determination of serum cytokine levels demonstrated that the imbalanced IL-6 production by T cells and the defective anti-tumour Th1 cell activity were related to elevated levels of IL-6 and IL-12. In vitro studies of PHA- and anti-CD3/anti-CD28 MoAbs stimulation of PBMC demonstrated the ability of lymphocytes from MM patients to differentiate towards the Th1 subset in the presence of rIL-12. By contrast, addition of exogenous rIL-6 impaired IFN-γ production by rIL-12-prompted T cells. Inhibition of Th1 polarization of the immune response by IL-6 was direct on T cells and not mediated by dendritic cells (DC). Evaluation of the ability of MM-derived DC to stimulate cell proliferation of allogenic T lymphocytes and produce IL-12 in vitro, in fact, suggested that MM-derived DC were functionally active. Taken as a whole, these results indicate that a deregulated cytokine network occurs in active MM. They also suggest that increased IL-6 production by peripheral T lymphocytes contributes to the immune dysfunction observed in MM, and enables tumour cells to escape immune surveillance by preventing the anti-tumour Th1 immune response.
NF-κB is involved in the regulation of CD154 (CD40 ligand) expression in primary human T cells
Authors: Srahna M , Remacle J E , Annamalai K , Pype S , Huylebroeck D , Boogaerts M A , Vandenberghe P 
Published: March 2003

SummaryCognate interactions between CD154 (CD40 ligand, CD40L) on activated T cells and its receptor CD40 on various antigen-presenting cells are involved in thymus-dependent humoral immune responses and multiple other cell-mediated immune responses. We have studied the regulation of CD154 expression in human T cells after activation with anti-CD3 and anti-CD28 antibodies or after pharmacological activation of protein kinase C with phorbol 12-myristate 13-acetate, and the calcium ionophore ionomycin. Under these conditions, transcription of the CD154 gene was rapidly induced without requiring de novo protein synthesis. Pharmacological inhibitors of NF-κB activation down-regulated CD154 mRNA and protein levels. Cyclosporin A, an inhibitor of NF-AT activation, acted similarly, and the effects of both inhibitors were additive. A potential NF-κB binding site is present within the CD154 promoter at positions −1190 to − 1181. In electrophoretic mobility shift assays, this sequence was specifically bound by NF-κB present in nuclear extracts from activated T cells. Furthermore, in transient co-transfection of Jurkat T cells, p65 activated the transcription of a reporter construct containing a multimer of this NF-κB binding site. These observations demonstrate a role of NF-κB transcription factors in the regulation of CD40L expression in activated primary human T cells.
HLA-A and HLA-B transcription decrease with ageing in peripheral blood leucocytes
Authors: Le Morvan C , Cogné M , Drouet M 
Published: March 2003

SummaryImmunosenescence involves modifications of humoral and cellular immunity. In a previous study, we have shown a locus-dependent reduction of HLA class-I cell surface expression on peripheral lymphocytes and monocytes with advancing age. Here we report the quantitative analysis of HLA-A and -B transcripts from PBL of 54 healthy subjects aged 21–90 years. Using a competitive RT-PCR method, we observed a significant decrease of HLA-A (P &lt; 0·0001) and -B (P = 0·0025) mRNA contents with increasing age. Secondly, to investigate this locus-dependent alteration of HLA class-I transcription, we performed EMSA using nuclear extracts from PBL of five young (24–31-year-old) and 5 elderly (58–69 years old) donors with locus A and B sequences of the Enh-A as probes. No qualitative variation of EMSA profiles appeared between the two groups of donors with 6 and 4 bandshift for the locus A and B, respectively. Quantitatively, we observed a significant increase of B4 intensity in the elderly group compared to the young group (P &lt; 0·05). These results suggest that the variation of DNA binding protein could contribute to the lower transcription of HLA-A and -B with ageing. These alterations of HLA class-I expression at the transcriptional level could lead to the unresponsiveness of CD8 T cells due to default of antigen presentation with ageing.
The proportion of Th1 cells, which prevail in gut mucosa, is decreased in inflammatory bowel syndrome
Authors: Van Damme N , De Keyser F , Demetter P , Baeten D , Mielants H , Verbruggen G , Cuvelier C , Veys E M , De Vos M 
Published: March 2003

SummaryT lymphocytes and their cytokines have an important role in the regulation of immune responses in the gut and in the pathogenesis of intestinal inflammation such as in Crohn's disease. The aim of this study was to analyse the Th1/Th2 cytokine profile (IFN-γ, IL-2, IL-4 and IL-10) in intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) in Crohn's disease (CD) and ulcerative colitis (UC) in relation to healthy controls (C). Colonic and ileal biopsy specimens were obtained from controls (n = 13) and patients with CD (n = 32). Colonic biopsies were obtained from patients with UC (n = 11). Intracytoplasmic IFN-γ, IL-2, IL-4 and IL-10 were determined by flow cytometry after PMA–ionomycin stimulation in IEL and LPL. In colonic LPL, a significant proportional decrease of IFN-γ and IL-2 producing CD3+ cells was observed in patients with CD and UC compared to controls. In ileal LPL, a similar tendency was found although differences were not significant. In IEL no differences in cytokine profiles could be observed. Flow cytometric analysis of intracytoplasmic cytokines at single cell level showed a proportional decrease of IFN-γ and IL-2 producing T cells in colonic lamina propria in patients with inflammatory bowel disease.
Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL)
Authors: Porakishvili N , Roschupkina T , Kalber T , Jewell A P , Patterson K , Yong K , Lydyard P M 
Published: March 2003

SummaryAbnormal CD4/CD8 ratios and T-cell function have previously been shown in patients with B-chronic lymphocytic leukaemia (B-CLL). We have demonstrated that CD4+ T cells containing both serine esterase and perforin (PF) are increased in the blood of these patients. Using flow cytometry, we have shown that the CD4+ PF+ cells were CD57+ but lacked expression of CD28, suggesting a mature population. The same phenotype in CD8+ T cells is characteristic of mature cytotoxic T cells. However, in contrast to the CD8+ T cells, the CD4+ T cells were more frequently CD45RO positive than CD45RA positive, indicating prior antigen experience. In contrast, this population lacked expression of either CD69 or HLA-DR, arguing that they were not activated or that they are an abnormal population of T cells. Their constitutive cytokine levels showed them mainly to contain IL4 and not IFNγ, suggesting a Th2 phenotype. The role of the CD4+ PF+ T-cell population is at present uncertain. However, this potentially cytotoxic T-cell population could contribute both to enhancing survival of the B-CLL tumour cells through production of IL4, and to the immunodeficient state frequently seen in patients with this tumour, independent of drug treatment.
Differential effect of phosphodiesterase inhibitors on IL-13 release from peripheral blood mononuclear cells
Authors: Yoshida N , Shimizu Y , Kitaichi K , Hiramatsu K , Takeuchi M , Ito Y , Kume H , Yamaki K , Suzuki R , Shibata E , Hasegawa T , Takagi K 
Published: March 2003

SummaryIncreased cyclic AMP (cAMP)-phosphodiesterase (PDE) activity in peripheral blood leucocytes is associated with the immunological inflammation that characterizes allergic diseases, such as atopic dermatitis and allergic rhinitis. Recently, it has been found that IL-13 has similar biological functions to IL-4. The aim of this study was to investigate the possible involvement of cAMP-PDE activity on IL-13 release from peripheral blood mononuclears cells (PBMC) from atopic asthma patients. Phytohaemagglutinin (PHA)-induced IL-13 release from PBMC was concentration-dependently inhibited by rolipram, a type 4 PDE inhibitor, as well as by dibutyryl cAMP, a membrane-permeant cAMP analogue. However, theophylline, a non-specific PDE inhibitor, and cilostazol, a type 3 PDE inhibitor, failed to inhibit IL-13 release. The inhibitory effect of rolipram was enhanced by the addition of forskolin (10−4m), an adenylyl cyclase stimulator. PHA itself did not alter the intracellular cAMP level. Rolipram concentration-dependently increased cAMP level in PHA-stimulated PBMC, and this increase was synergistically facilitated by the addition of forskolin (10−4m). These results suggest that type 4 PDE inhibitors, alone or synergistically in combination with forskolin, inhibit PHA-induced IL-13 release from PBMC of atopic asthma patients by elevating intracellular cAMP concentrations. These inhibitors have the potential to exert an anti-inflammatory effect by inhibiting IL-13 production in allergic diseases such as atopic asthma.
Lack of age-associated LFA-1 up-regulation and impaired ICAM-1 binding in lymphocytes from patients with Down syndrome
Authors: Lin S-J , Wang J-Y , Klickstein L B , Chuang K-P , Chen J-Y , Lee J-F , Shieh C-C 
Published: March 2003

SummaryTo investigate the role of LFA-1 in the immune defects in DS patients, we analysed lymphocytes from DS patients in LFA-1 expression and LFA-1 mediated cell adhesion. DS patients less than 2 years of age expressed a higher level of LFA-1 when compared with age-matched controls. The difference in LFA-1 expression was much less significant in older DS patients when compared with age-matched children. Although older children (2–15-year-old groups) without DS tend to increase their expression of lymphocyte LFA-1 when compared with younger normal children (0–2 years old), DS patients showed no age-associated increase in lymphocyte LFA-1 expression. Two-colour analysis with CD4/CD8 and LFA-1 in patients and controls showed that proportions of CD4 + lymphocytes were comparable in DS patients and controls, while the proportion of CD8 + lymphocytes was higher in older DS patients. Expression levels of LFA-1 on both CD4 + and CD8 + lymphocytes in younger DS patients were higher when compared with age-matched controls and close to the expression levels in the older DS group. Proportions of memory lymphocytes expressing the CD45RO isoform were higher in both younger and older DS patients when compared with age-matched control groups. Noticeably, the LFA-1 expression levels on CD45RO lymphocytes from younger DS patients were higher than the levels of the controls and declined in the older DS group. We tested lymphocytes (EBV transformed B cells, resting and anti-CD3 stimulated T cells) for cellular adhesion to recombinant ICAM-1 and found that lymphocytes from DS patients were less adhesive, even though their β2 integrin expression was comparable with that of normal controls. These results suggest that more generalized pathological processes, such as early senescence of the immune system or ineffective lymphocyte activation, and subsequent integrin dysfunction may underlie the immune defects in DS patients.
Interferon-γsecretion of peripheral blood CD8+ T lymphocytes in patients with bronchial asthma:In vitrostimulus determines cytokine production
Authors: Biller H , Bade B , Matthys H , Luttmann W , Virchow J C 
Published: March 2003

SummaryIt has been postulated that T lymphocytes orchestrate the chronic inflammation in bronchial asthma. In animal models, infiltration of CD8+ T lymphocytes into the bronchial mucosa prevented bronchial hyperresponsiveness and decreased early and late phase reaction. IFN-γ antagonizes IL-4-dependent IgE production as well as IL-5-induced proliferation and activation of eosinophils. We therefore investigated the secretion of IFN-γ of isolated CD8+ T lymphocytes from peripheral blood of patients with allergic asthma (n = 6) and from healthy controls (n = 7) in vitro. In this setting we compared the effect of stimulation with anti-CD3 antibodies with that of phorbol myristate acetate (PMA) and calcium-ionophore. As expected, CD8+ T lymphocytes from peripheral blood of healthy volunteers produced significantly more IFN-γ in the presence of PMA and calcium-ionophore than after stimulation with anti-CD3 antibodies. However, in subjects with allergic asthma, IFN-γ secretion of CD8+ T cells was significantly higher when incubated with anti-CD3 antibodies than after activation with PMA and calcium-ionophore. While IFN-γ secretion of CD8+ T lymphocytes of patients with allergic asthma was lower than that of healthy controls in the presence of PMA/calcium-ionophore, it was significantly elevated when compared with normal controls after stimulation with anti-CD3 antibodies. Thus, potent activators of cytokine secretion, such as PMA and calcium-ionophore, induce a cytokine profile different from that induced by weaker stimulants, such as anti-CD3 antibodies. These findings have implications for further studies investigating cytokine production of inflammatory cells in vitro.
Characterization ofHerpesvirus saimiri-transformed T lymphocytes from common variable immunodeficiency patients
Authors: CABANILLAS J A , CAMBRONERO R , PACHECO-CASTRO A , GARCÍA-RODRÍGUEZ M C , MARTÍN-FERNÁNDEZ J M , FONTÁN G , REGUEIRO J R 
Published: March 2003

SummaryCommon variable immunodeficiency (CVID) is a very frequent but heterogeneous syndrome of antibody formation. The primary defect remains unknown, but many reports describe peripheral blood T lymphocyte dysfunctions in a substantial proportion of CVID patients, which may impair T–B cell collaboration. In order to investigate whether such putative defects were intrinsic to T cells or, rather, secondary to quantitative differences in T cell subset distribution, or to other described disorders, we have used Herpesvirus saimiri (HVS) for the targeted transformation of CVID CD4+ and CD8+ T cells and subsequent functional evaluation by flow cytometry of their capacity to generate cell surface (CD154, CD69) or soluble (IL-2, TNF-α, IFN-γ) help after CD3 engagement. Unexpectedly, the results showed that 40 different CVID blood samples exposed to HVS gave rise with a significantly increased frequency to transformed CD4+ T cell lines, compared to 40 age-matched controls (27%versus 3%, P≤ 0·00002) suggesting the existence of a CVID-specific signalling difference which affects CD4+ cell transformation efficiency. The functional analysis of 10 CD4+ and 15 CD8+ pure transformed T cell lines from CVID patients did not reveal any statistically significant difference as compared to controls. However, half of the CD4+ transformed cell lines showed CD154 (but not CD69) induction (mean value of 46·8%) under the lower limit of the normal controls (mean value of 82·4%, P≤ 0·0001). Exactly the same five cell lines showed, in addition, a significantly low induction of IL-2 (P≤ 0·04), but not of TNF-α or IFN-γ. None of these differences were observed in the remaining CD4+ cell lines or in any of the transformed CD8+ cell lines. We conclude that certain CVID patients show selective and intrinsic impairments for the generation of cell surface and soluble help by CD4+ T cells, which may be relevant for B lymphocyte function. The transformed T cell lines will be useful to establish the biochemical mechanisms responsible for the described impairments.
Smoking and disease severity are independent determinants of serum adhesion molecule levels in Graves’ ophthalmopathy
Authors: WAKELKAMP I M M J , GERDING M N , MEER J W C VAN DER , PRUMMEL M F , WIERSINGA W M 
Published: March 2003

Summary
Adhesion molecules play a key role in autoimmune disorders, and serum concentrations of soluble adhesion molecules are increased in Graves’ ophthalmopathy (GO). Whether this is due to the strong association with smoking is unknown. It is also not known if the severity or activity of GO determine the serum levels of adhesion molecules. We measured serum concentrations of sICAM-1, sVCAM-1 and sELAM-1 in 62 euthyroid Graves’ patients with untreated GO, in 62 healthy controls matched for sex, age and smoking habits, and in 26 euthyroid Graves’ patients without GO. GO severity was assessed by the Total Eye Score and the activity by the Clinical Activity Score. Adhesion molecules were measured by highly sensitive ELISAs. GO patients had higher levels than controls (median values in ng/ml with range): sICAM-1 300 [171–575] versus 244 [119–674], P &lt; 0·001; sVCAM-1 457 [317–1060] versus 410 [238–562], P &lt; 0·001; and sELAM-1 61 [19–174] versus 53 [23–118], P = 0·021. Euthyroid Graves’ disease patients without GO had levels similar to controls: sICAM-1 273 138–453), sVCAM-1 386 [260–1041] and sELAM-1 46 [22–118]. Smoking had an independent effect and was associated with higher levels of sICAM-1 and lower levels of sVCAM-1 in both GO patients and controls; sELAM-1 levels were comparable. In the 62 GO patients, sICAM-1 correlated significantly with severity of eye disease (r = 0·40, P = 0·002). No correlation was found with the duration of GO, the Clinical Activity Score or TBII levels. Multivariate analysis of all 150 subjects showed that the presence of GO and smoking are independent determinants of sICAM-1 and sVCAM-1 concentrations. In GO patients, the Total Eye Score was a stronger determinant than smoking. It is concluded that (i) smoking is associated with increased sICAM-1 and decreased sVCAM-1 levels; (ii) independent from smoking, euthyroid GO patients have higher levels of sICAM-1, sVCAM-1 and sELAM-1 than patients with euthyroid Graves’ disease or healthy controls; (iii) the major determinant of sICAM-1 in GO patients is the severity of their eye disease.
The CD28/HLA-DR expressions on CD4+T but not CD8+T cells are significant predictors for progression to AIDS
Authors: Choi B-S. , Park Y-K , Lee J-S 
Published: March 2003

SummaryTo investigate the changes of CD28 and HLA-DR molecules on CD4+ and CD8+ T cells during HIV infection, we classified 130 HIV-infected Koreans into four groups by the CD4 level as follows: group I (≥500 cells/mm3), group II (201–499 cells/mm3), group III (51–200 cells/mm3), and group IV (≤50 cells/mm3). In CD4+ T cells, the proportion of CD28 expression decreased significantly with the CD4 level while the proportion of HLA-DR expression increased gradually. In particular, the changes of HLA-DR expressions on CD4+ T cells were parallel to the loss of CD28 molecules from stage III to IV. However, the CD28 expression on CD8+ T cells decreased dramatically in the early stage of HIV infection, and the sum and pattern of CD28 and HLA-DR expressions on CD8+ T cells was stable after the first stage. Even though CD28 down-regulation on CD8+ T cells was very severe from the early stage of HIV infection, it might not influence the survival time of HIV-infected Koreans. The sum of the CD28+ subsets and HLA-DR subsets in each T cell was stable in all stages of disease progression. The sums of the CD28+ subsets and HLA-DR+ subsets in CD4+ T and CD8+ T cells were constant as approximately 100% and 55–60% of each T cell. These results suggested that the changes of CD28/HLA-DR expressions on CD4+ T cells were more predictable than those on CD8+ T cells in the evaluation of the disease progression during HIV-infected periods. However, we need further studies to understand why the sum of two molecules in each T cell are constant.
Complement activation in infective endocarditis: correlation with extracardiac manifestations and prognosis
Authors: MESSIAS-REASON I J , HAYASHI S Y , NISIHARA R M , KIRSCHFINK M 
Published: March 2003

SummaryIn an infectious process complement activation is necessary for a proper immune and inflammatory response, but when exacerbated may cause tissue injuries. In infective endocarditis (IE) patients tend to develop high titres of circulating immune complexes (CIC) that activate complement. The aim of this study was to evaluate for the first time complement activation in IE for possible correlation with extracardiac manifestations and clinical prognosis. Twenty patients with IE, 14 healthy controls and 15 patients presenting mitral and aortic valve lesions (with no signs of either infection or other associated diseases), were studied. Plasma levels of C3adesArg, SC5b-9, C1rs-C1Inh and C3b(Bb)P were determined by ELISA and C3d by double decker immunoelectrophoresis. C3 and C4 levels were assayed by turbidimetry and CIC by ELISA. Elevation of plasma levels of all complement activation products, with the exception of C3b(Bb)P, indicated a significant classical pathway activation in IE patients when compared to controls (C3d: P &lt; 0·00004; C3adesArg: P &lt; 0·03, SC5b-9: P &lt; 0·01, C1rs-C1Inh: P &lt; 0·00007). CIC levels were significantly increased (P &lt; 0·005) and C3 reduced in IE patients (P &lt; 0·05). Elevated C3d (P &lt; 0·02) and C3adesArg (P &lt; 0·03) levels were associated with pulmonary manifestations. In addition, C3d was significantly elevated in the patients who died when compared to those who had a good recovery (P &lt; 0·02). Our data demonstrate the activation of the complement classical pathway, most probably mediated by CIC, in IE and suggests C3d and C3adesArg as possible markers for extracardiac lesion and severity of the disease.
Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs
Authors: STRAUSS G , OSEN W , DEBATIN K-M 
Published: March 2003

SUMMARYImmunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graft-versus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigen-specific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.