Competition between IL-1, IL-1ra and TGF-beta 1 modulates the response of the ELA4.NOB-1/CTLL bioassay: implications for clinical investigations.

Objective: The use of ELISA techniques to measure cytokine levels in clinical samples has chiefly replaced more labour intensive bioassays. ELISA measurements, however, do not reflect the functional activity of a cytokine within a sample; interleukin-1 (IL-1), for example, has two agonist isoforms (IL-1 alpha and IL-1 beta) and a competitive receptor antagonist (IL-1ra), and can be regulated by transforming growth factor beta1 (TGF-beta 1). The net effect of these cytokines, rather than IL-1 levels, are frequently suggested to regulate tissue inflammation, but confirming this has been difficult.

Functional interactions between mucosal IL-1, IL-ra and TGF-beta 1 in ulcerative colitis.

Objective: Studies aiming to define key cytokines in inflammatory bowel disease have been restricted to gene expression or protein quantitation but lack functional information on cytokine interactions. Some of the major cytokines that govern the extent and duration of the inflammatory process in ulcerative colitis (UC), appear to be interleukin 1 (IL-1), its natural inhibitor IL-1 receptor antagonist (IL-1ra) and transforming growth factor beta1 (TGF-beta 1). Indeed, as a predictor of inflammation, the mucosal status of IL-1, depicted as a ratio of IL-1ra/IL-1, has often been used.

Circular polarization of light by planet Mercury and enantiomorphism of its surface minerals.

Different mechanisms for the generation of circular polarization by the surface of planets and satellites are described. The observed values for Venus, the Moon, Mars, and Jupiter obtained by photo-polarimetric measurements with Earth based telescopes, showed accordance with theory. However, for planet Mercury asymmetric parameters in the circular polarization were measured that do not fit with calculations.

Diagnostic and prognostic importance of T-cell receptor gene analysis in patients with Sézary syndrome.

Background: Sézary syndrome (SS) is characterized by erythroderma, peripheral lymphadenopathy, and circulating Sézary cells and is clinically heterogeneous.

Methods: T-cell receptor (TCR) gene analysis was performed using DNA extracted from peripheral blood mononuclear cells from 74 patients, and the results were correlated with a variety of other diagnostic parameters and patient outcomes.

Results: Two groups were identified: 66 patients with clonal TCR gene rearrangement (clonal patients) detected with Southern blot analysis and/or polymerase chain reaction/single-strand conformational polymorphism analysis and 8 patients with no clonal rearrangement detected (nonclonal patients) using either technique.

Highly active antiretroviral therapy normalizes the potential for MIP-1alpha production in HIV infection.

Design: The CC chemokines RANTES, MIP-1alpha and MIP-1beta are ligands for CCR5, which has been identified as the principal co-receptor for macrophage tropic strains of HIV-1. This study investigated whether the inducible levels of RANTES, MIP-1alpha and MIP-1beta produced by cultured whole blood samples related to different rates of progression of HIV infection and to the introduction of Nelfinavir-based highly active anti-retroviral therapy (HAART).

Methods: Study subjects were HIV-positive and categorized as "slow progressors" (n= 8) or as "fast progressors" (n= 7); the latter group were treated with HAART.

Immune potentiation of ultrafine dietary particles in normal subjects and patients with inflammatory bowel disease.

Various specific and non-specific environmental factors have been associated with the induction and/or exacerbation of disease activity in patients with Crohn's disease and ulcerative colitis. One such factor is the potential role of ingested ultrafine particles. In fact, based on a Western diet, recent data suggest that more than 10(12)ultrafine particles are ingested per person every day.

Rapid cytokine up-regulation of integrins, complement receptor 1 and HLA-DR on monocytes but not on lymphocytes.

Short-term (3 hr) incubation of whole blood with human recombinant cytokines induced rapid changes in the expression of monocyte but not of lymphocyte surface molecules. The percentage of monocytes bearing CD11b molecules was enhanced by tumour necrosis factor-beta (TNF-beta), whilst that of CD11c was increased by both TNF-alpha and TNF-beta. The mean fluorescence intensity (MFI) of monocyte CD11a was enhanced by interleukin-2 (IL-2), TNF-alpha and TNF-beta, and that of CD11b, CD11c and CD18 was increased by IL-2, IL-4, TNF-alpha and TNF-beta.

Dose-related effects of oestradiol on rat thymic and splenic T-lymphocyte responsiveness to mitogens.

The dose-related effects of oestradiol on responses of thymic and splenic lymphocytes to mitogenic stimulation were studied in immature female Wistar rats. An attempt was made to relate responses not merely to dose but also to the circulating levels of the steroid. Lymphocytes were prepared from thymus and spleen and stimulated with phytohaemagglutinin (PHA) and concanavalin A (Con A) prior to measurement of 3H-thymidine incorporation.

Cytokines in human intraocular inflammation.

The presence of interleukin 6 (IL-6), interleukin 1 (IL-1), interleukin 2 (IL-2) and tumour necrosis factor (TNF) was investigated in vitreous and aqueous aspirates from eyes undergoing vitrectomy for the treatment of different inflammatory conditions. Cadaveric vitreous from 10 normal subjects were used as controls. IL-6 was observed in 5 specimens from eyes with idiopathic uveitis (range = 26-264 pg/ml), in 2 specimens from eyes with uveitis complicated with retinal detachment (28 and 279 pg/ml, respectively), in 6 samples from eyes with diabetic retinopathy (range = 5-480 pg/ml), in one sample from an eye with phacolytic glaucoma (1190 pg/ml) and in one specimen from an eye with Behçet's disease (366 pg/ml).

Selective up-regulation of human granulocyte integrins and complement receptor 1 by cytokines.

The percentage of human granulocytes expressing the integrins CD11b and CD11c as well as complement receptor 1 (CD35) was increased by short-term incubation of whole blood with interleukin-2 (IL-2), interleukin-4 (IL-4) and tumour necrosis factors alpha and beta (TNF-alpha and TNF-beta). The mean fluorescence intensity of granulocyte CD18 was also increased by the above cytokines, whilst that of CD11b was only increased by TNF-alpha. Up-regulation of granulocyte CD18 expression was seen with 1 U/ml of IL-2, TNF-alpha or TNF-beta, in contrast to the effect of IL-4 which was only observed with 100 U/ml.

The influence of zinc status and malnutrition on immunological function in Crohn's disease.

Cellular immunity is likely to be important in the pathogenesis of Crohn's disease; whether it is abnormal is not clear. The heterogeneity of patients with Crohn's disease probably underlies the disparity of reports, but attempts to determine which clinical features influence cellular immunity have been largely unsuccessful. This is probably caused by the omission of nutritional status as a potential factor, even though zinc deficiency has frequently been linked with abnormal immunity.

Cytokines in proliferative vitreoretinopathy.

This study determined the presence of interleukin 1 (IL-1), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF alpha), tumour necrosis factor beta (TNF beta), interferon gamma (IFN gamma), transforming growth factor beta 2 (TGF beta 2) and fibroblast proliferation activity (FPA) in vitreous aspirates from eyes undergoing vitrectomy for the treatment of retinal detachment complicated by proliferative vitreoretinopathy (PVR) or uncomplicated retinal detachment (RD). Cadaveric vitreous from normal subjects were used as controls. The results showed that IL-1 and IL-6 predominated in vitreous from eyes with PVR or RD, and that concentrations of IL-6 greater than 20 pg/ml were more frequently found in PVR than in RD (p = 0.

Release of cytokines during generation of lymphokine-activated killer (LAK) cells by IL-2.

Supernatants of IL-2-activated mononuclear cells (MNC) that displayed an optimal lymphokine-activated killer (LAK) cell activity at 48-72 hr in culture were found to contain increased levels of tumour necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interferon-gamma (IFN-gamma) when compared with supernatants from mononuclear cells cultured in the absence of IL-2. The concentration of TNF alpha and IL-1 alpha produced by MNC at 24 hr was either increased or maintained by extending the cultures to 96 hr. In contrast, TNF beta was only detected at very low levels after 72-96 hr culture, irrespective of whether IL-2 was present or absent.

A phase I study of immunostimulation and toxicity in patients with colorectal carcinoma using the immunomodulator 3,6-bis(2-piperidinoethoxy) acridine trihydrochloride (CL 246738).

Seventeen patients with residual or recurrent colorectal carcinoma were given a new synthetic immunomodulator [3,6-bis(2-piperidinoethoxy) acridine trihydrochloride CL246738) as part of a phase I clinical trial. No patients had undergone previous immunotherapy or chemotherapy. Detailed immunological studies including interferon levels, interleukin 2 levels, natural killer cell function, mitogen responses of lymphocytes, immunoglobulin levels and lymphocyte subpopulation levels were analysed in the patients who received this drug in an attempt to find out whether there was any biological activity identifiable in humans.

The production of arthritis in the guinea-pig by intra-articular reaction between lymphokines and inflammatory leucocytes.

A single intra-articular injection of lymphokine into the guinea-pig knee joint resulted in a sequence of changes in joint architecture whose histopathological features resembled that of an acute inflammatory reaction progressing to a chronic state. At 24 h there was a mild hyperplasia and hypertrophy of the synovium with intense polymorphonuclear leucocyte infiltration. At 72 h, the synovium was heavily infiltrated with diffuse and focal aggregations of mononuclear cells; erosion of cartilage and bone by synovial pannus was accompanied by a subsynovial fibrosis.

Adoptive immunotherapy administered via the hepatic artery and intralesional interleukin-2 in hepatocellular carcinoma.

We assessed the feasibility of using lymphokine-activated killer cells (adoptive immunotherapy) with infusions of interleukin-2 when given regionally in three patients with unresectable primary hepatocellular carcinoma (PHC). In 2 patients, 2 cycles, which included a bolus of LAK (10(7) to 10(8) cells followed by a 4-hourly infusion of IL-2 were administered via selective arterial catheterization of the hepatic artery. One further patient received 3 cycles of IL-2 alone by direct intralesional and perilesional injections.

Thymosin, interleukins, isoprinosine and imuthiol do not reconstitute T-cells in athymic nude mice.

Previous reports suggest that immunotherapy can induce T-cell development in athymic nude mice. Eight-week-old BALB/c nu/nu (athymic nude) mice were treated for 3, 6 and 12 weeks with thymosin fraction 5 (TF-5), buffy coat interleukins (BC-IL), recombinant IL-2 (rIL-2), a combination of TF-5 and BC-IL, isoprinosine or imuthiol. Control animals were treated with sterile saline or were given a syngeneic thymus graft.

Modulation of Fc and C3b receptor expression on guinea-pig macrophages by lymphokines.

The decrease in Fc-receptor-positive cells that occurred during a 6 h incubation of resident and elicited guinea-pig macrophages was partly abrogated when lymphokines were present in the culture. When the same lymphokine preparations were tested on C3b receptor-expression they preferentially sustained the percentage of C3b rosettes formed by resident rather than elicited macrophages. This lymphokine-induced maintenance of Fc and C3b rosettes by cultured macrophages may have been due to an inhibition of receptor release or an increase in receptor synthesis.

Interleukin-1 and interleukin-2 activity in chronic hepatitis B virus infection.

Abnormalities of lymphocyte proliferation in chronic hepatitis B virus infection are well documented, although the underlying mechanisms are poorly understood. To determine whether these defects may be secondary to disordered lymphokine production, we have simultaneously assayed interleukin-1 and interleukin-2 production in 31 chronic carriers of the hepatitis B virus. Supernatants from mononuclear cells cultured both in the presence and absence of lipopolysaccharide contained significantly increased quantities of interleukin-1 activity in patients compared with normal controls (p less than 0.

Polymorphonuclear leucocytes in Crohn's disease and ulcerative proctocolitis: association between enhanced adherence to nylon fibre and disease variables.

The adherence of polymorphonuclear leucocytes (PMN) to nylon fibre was investigated in patients with Crohn's disease, ulcerative proctocolitis, and anorexia nervosa, and compared with changes of circulating PMNs, C reactive protein concentrations, erythrocyte sedimentation rates, and clinical assessment of disease activity. PMN adherence was in excess of the maximum value detected for healthy subjects in 14 of 25 patients with Crohn's disease and two of 10 with proctocolitis, but it was within the normal range for all eight with anorexia nervosa. High adherence in Crohn's disease, however, was not associated with quantitative or qualitative changes of PMN populations, absolute concentrations of C reactive protein, erythrocyte sedimentation rates, disease severity, drug regimens, malnutrition, or zinc deficiency.

Shedding and synthesis de novo of Fc and C3b receptors by cultured guinea-pig macrophages.

Resident macrophages freshly obtained from the peritoneal cavity of guinea-pigs were demonstrated to form a higher percentage of Fc and C3b rosettes than elicited macrophages when low concentrations of IgG and IgM-C3b were used to sensitize ox red blood cells (ORBC) in rosette assays. Culture of the total resident and elicited macrophages for 6 h at 37 degrees C resulted in a decrease of Fc and C3b rosette-forming cells, the loss of Fc receptor-bearing cells by resident macrophages only being apparent when using a sub-optimal concentration of sensitizing IgG. After 24 h incubation the percentages of Fc and C3b rosettes returned to their initial values.

Analysis of human lymphocyte transformation responses to graded doses of T cell mitogens by curve fitting.

The between-group comparison of complete lymphocyte transformation dose-response curves is complex. We have therefore derived a mathematical model of the dose-response characteristics of human mononuclear cells to stimulation by concanavalin A (ConA) and purified phytohaemagglutinin (PHA), in order to simplify such analyses. This model describes dose-response curves in terms of the magnitude of the peak response, the dose of mitogen that elicits the peak and an estimate of the range of mitogen doses which induce a response.

Failure of exogenous interleukin 1 and interleukin 2 to correct decreased lymphocyte transformation in chronic hepatitis B virus carriers.

To test the hypothesis that reduced lymphocyte transformation in response to PHA in chronic hepatitis B virus infection might be due to deficient lymphokine production, lymphocyte transformation was measured in the presence or absence of exogenous interleukin 1, interleukin 2 or both, or, as a source of mixed lymphokines, supernatants from mixed lymphocyte reactions. The response to PHA was significantly impaired in patients compared to controls, but was not corrected by interleukin 1, interleukin 2 or supernatant from mixed lymphocyte reactions over a wide range of concentrations. Variation of the proportion of monocytes in culture or the addition of indomethacin had no effect on lymphocyte transformation.

Interleukin 1 in Crohn's disease.

A number of the activities currently ascribed to the mediator interleukin 1 (IL-1) are relevant to chronic inflammatory bowel disease. Using the mouse thymocyte stimulation assay, lymphocyte-activating factor (LAF) activity was measured in plasma samples and supernatants from cultures of peripheral blood mononuclear cells from 16 patients with Crohn's disease, six with ulcerative colitis, and 10 healthy subjects. Results were compared with disease activity, drug therapy, granulocyte count, and plasma levels of zinc and C-reactive protein (CRP).

Cell-mediated immunity in anorexia nervosa.

Twelve patients with anorexia nervosa were studied for cell-mediated immunity in terms of delayed hypersensitivity reactions to recall antigens, lymphocyte transformation responses to T-cell mitogens, and numbers of circulating leucocytes and T-cell subpopulations. Compared to controls, all patients had reduced cutaneous reactions and four were anergic. There was a mild leucopenia in patients and both T4+ and T3+ numbers were slightly reduced.