New glucocorticoids. Mechanisms of immunological activity at the cellular level and in the clinical setting.
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Biomedical subjects
Publications and source records attributed to F Indiveri.
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HLA Class I soluble antigen serum levels have been evaluated in 178 subjects who were positive for human immunodeficiency virus (HIV) and in 66 HIV-negative controls. The serum levels of HIV p24 antigen, interleukin 2 receptor (IL 2r), CD8 soluble antigen (CD 8ag), B2-microglobulin (B2-m), and neopterin (Npt), as well as the number of CD4+ and CD8+ T cells were also evaluated. Results show that mean HLA class I serum levels of HIV-positive subjects: (1) are significantly higher than controls (p less than 0.001); (2) increase with disease progression (67.7 RU/ml, 103.4 RU/ml, and 169.6 RU/ml for subjects belonging to groups II, II, and IV of the Centers for Disease Control [CDC] classification, respectively); (3) correlate with HIV p24 antigen, IL2r, and CD 8 soluble antigen levels. Present data show that elevated levels of HLA class I soluble antigens, correlating with disease stage, are found in sera of HIV-positive subjects. Circulating HLA class I molecules, interfering with some immune functions, might contribute to the pathogenesis of the immune deficiency of HIV-positive subjects.
alpha-Endorphin (aEP) inhibited the expression of HLA-Class II antigens by PHA-primed T lymphocytes and reduced mitogen-induced T-cell proliferation up to 35%. This action was time related and not naloxone sensitive. When aEP was added to autologous and allogeneic lymphocyte cultures (both of non-T/T and T/T type), it inhibited lymphocyte blastogenesis up to 40%. These findings, indicating that aEP can influence some functions of immunocompetent cells, provide evidence for the functional interrelationship between the neuroendocrine and the immune systems.
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AIDS patients often develop a conspicuous although functionally ineffective hypergammaglobulinaemia. We have treated four patients affected by AIDS or AIDS-related complex (ARC) with repeated courses of plasmaexchange coupled with immunoglobulin infusions. The schedule of each course was as follows: one plasmapheresis treatment once a week for 5 consecutive weeks, each treatment amounting to an average exchange of 3000 ml of plasma, replaced by plasma/protein and 5% albumin/physiological saline solutions, and followed by infusion of 15 gr of human immunoglobulins. Each plasmapheresis course was completed by additional weekly administrations of the same amount of human immunoglobulins. In each patient we noted fast cessation of fever, weight gain, and an overall clinical amelioration with decrease of infections, asthenia, and anorexia. Haematological, serological, and immunological parameters (particularly IgG serum levels) also significantly improved after treatment.
Some serological (serum immunoglobulins, circulating immune complexes, quantitative assessment of hemolytic complement activity) and cellular (total number of circulating lymphocytes as well their phenotypic and functional characterization) parameters have been analyzed in 42 patients with lung cancer of three hystologic types and in 19 healthy controls to define whether different histologic neoplasms have an impact on the host immune system. As a group, cancer patients showed 1) the presence of circulating immune complexes, in a significant percentage, within all the three groups studied; and 2) a significant reduction of lymphocytes forming E rosette. With regard to cellular immune parameters we noted that 1) T lymphocytes isolated from the peripheral blood lymphocytes (PBL) of patients with lung cancer showed a decreased capacity to express HLA-class II antigens upon phytohemogglutinin (PHA) activation in vitro; 2) PBL from lung cancer, in particular the adenocarcinoma group, failed to proliferate upon stimulation by policlonal mitogens; and 3) the autologous mixed lymphocyte reaction (MLR) of non-T/T-type was impaired in all three groups, whereas the autologous MLR of T/T-type was impaired only in the patients with squamous cell carcinoma and in those with adenocarcinoma, probably as a result of a reduced stimulatory capacity.
Deflazacort (DFC) is a new glucocorticoid which, when compared with prednisone (PDN), has similar anti-inflammatory actions, but lacks several unwanted side effects on mineral and carbohydrate metabolism. DFC is more efficient than PDN in inducing immunomodulatory effects. This study concerns twelve patients with classical RA who required corticosteroid therapy because of the ineffectiveness of other drugs. Six patients received 12 mg/day of PDN from day 1 to day 21 and 15 mg/day of DFC from day 29 to day 50. The second group of six patients received DFC initially followed by the PDN dosing regimen. At various times (4, 8, 24, 48 and 72 h) after the first administration of steroid, and 7, 14 and 21 days after the beginning of the treatment with PDN or DFC the following tests were performed the phenotype of T lymphocytes isolated from peripheral blood; the evaluation of the expression of HLA Class 2 antigens by PHA primed T cells; and the analysis of cell behavior in mixed lymphocyte reactions. The data reported in this paper show that the oral administration of DFC to patients with RA affects the in vitro behavior of their lymphocytes. This immunomodulatory effect of DFC concerns both the phenotype and function of RA lymphocytes. Moreover it differs in both intensity and kinetic characteristics from the immunomodulating effect observed with PDN (control).
In the present study both responsiveness and stimulatory capacity in autologous mixed lymphocyte reactions (AMLRs) of non-T/T and T/T type, as well as in allogeneic mixed lymphocyte reaction (MLR), were evaluated in 30 intravenous drug abusers (IDAs) infected by the human immunodeficiency virus (HIV) and in 10 HIV-negative IDAs. The production of interleukin 2 (IL2), and the expression of HLA Class II antigens and IL2 receptors by PHA-activated T lymphocytes were also evaluated. A severe impairment of both responsiveness and stimulatory capacity in MLR and AMLRs was found in the HIV-positive IDAs and not in the HIV-negative IDAs. The HIV-positive IDAs showed also a defective expression of HLA Class II antigens, whereas the IL2 production and the IL2 receptor expression were in the normal range. The present data are consistent with similar observations in male homosexuals with AIDS-related complex and confirm that the HIV infection induces a broad spectrum of immunological abnormalities leading to a progressive derangement of the immunocompetence.
The expression of HLA Class II antigens by resting and phytohemagglutinin (PHA)-activated T cells and their functional properties in autologous mixed-lymphocyte reactions (MLR) were investigated in patients with chronic active hepatitis, with alcoholic cirrhosis, and with primary biliary cirrhosis. In all groups of patients the percentage of resting T cells expressing HLA Class II antigens was significantly higher than that in controls. The percentage of T cells which acquired HLA Class II antigens following PHA stimulation was reduced in patients with chronic active hepatitis, serum hepatitis B surface antigen (HBsAg) positive, and in those with alcoholic cirrhosis, HBsAg negative, although the level of [3H] thymidine incorporation was within normal limits. The degree of proliferation in autologous MLR with PHA-T cells was significantly reduced in patients with chronic active hepatitis, HBsAb positive, and in those with alcoholic cirrhosis, HBsAg positive. A reduced proliferation was also detected in autologous MLR with non-T cells, in patients with chronic active hepatitis, HBsAg positive. The abnormalities of autologous MLR are selective, since the proliferative and stimulatory activities of cells from patients with chronic liver diseases in allogeneic MLR were within normal ranges. The immunoregulatory role of HLA Class II antigens and of autologous MLR suggests that the abnormalities we have identified may play a role in the immunological dysfunctions underlying chronic liver diseases.
A reduced percentage of T cells isolated from mediastinal lymph nodes and peripheral blood of patients with lung carcinoma acquired HLA Class II antigens following in vitro stimulation with PHA. Furthermore T cells were functionally abnormal in autologous and allogeneic mixed lymphocyte reactions (MLR). The immunoregulatory properties of HLA Class II antigens and autologous MLRs suggest that these abnormalities may affect the interaction of the host's immune system with tumor cells.
Analysis of T cells from patients with systemic lupus erythematosus (SLE) and with rheumatoid arthritis (RA) identified a deficit in the induction of HLA Class II antigens by PHA although the proliferative response was normal and in the [3H]thymidine incorporation in autologous mixed lymphocyte reactions (MLR) with PHA-T cells as stimulators. In RA these abnormalities were more marked in patients with active disease than in those in clinical remission. The deficit of autologous MLR with PHA-T cells was more marked than that of autologous MLR with non-T cells and of allogeneic MLR. Serum from patients with SLE and with RA did not display any detectable inhibitory activity on the induction of HLA Class II antigens by PHA, on the proliferative response of lymphocytes to PHA, on autologous MLR with PHA-T cells and with non-T cells as stimulators and on allogeneic MLR. These results suggest that the abnormalities we have identified reflect an intrinsic defect of T cells.
While high doses of hydralazine inhibit the proliferative response of T lymphocytes to mitogens and antigens, low doses (0.15 microgram/ml) selectively enhance the proliferative response of T cells to autologous non-T cells. The effect is especially pronounced on lymphocytes which express the HLA-DR4 allospecificity. These results suggest that the autologous mixed lymphocyte response with non-T cells may represent a useful in vitro model to analyse the mechanism(s) of the immunologic abnormalities induced by hydralazine.
MDL-899 is new phthalazine derivative which has been developed as a substitute for hydralazine, which has several undesirable effects, in the treatment of hypertension. The effects of MDL-899 on human lymphocyte functions are analyzed. This drug inhibited in a dose-related fashion the blastogenesis of lymphocytes upon PHA and Con A activation and down-regulated the activation of allogeneic mixed lymphocyte reactions (MLR). On the contrary the drug enhanced the activation of autologous MLR of non T/T type. This effect was five times higher on cells which carried the HLA DR 4 phenotype. The above reported observations suggest that MDL-899, as well as hydralazine, affects the in vitro responsiveness of human lymphocytes mostly in subjects with HLA-DR 4 phenotype. Whether the impact of MDL-899 on immune function gives rise to a lupus like syndrome is not known. For this reason further studies are warranted to assess its long-term in vivo effects.
The degree of proliferation of human T cells stimulated with autologous PHA-T cells and with autologous non-T cells displays circadian variations. The highest proliferation occurs with cells isolated from blood drawn at 8 a.m. in mixed lymphocyte reactions (MLR) with autologous PHA-T cells and from blood drawn at 8 p.m. in MLR with autologous non-T cells. The circadian variations of autologous MLRs appear to reflect changes in the proliferative response of T cells. In autologous MLRs with non-T cells as stimulators the extent of proliferation was inversely correlated with the level of endogenous cortisol. The circadian variations of autologous MLRs do not reflect non-specific changes in the proliferative and stimulatory properties of T and non-T cells, since circadian variations were not observed in the proliferative response of T cells to mitogens and in allogeneic MLRs. Circadian variations of autologous MLRs must be taken into account when analyzing abnormalities of these reactions in pathological conditions.
Since conflicting results have been reported about the role of xenoantigens in the proliferation of T cells stimulated with autologous non-T cells, the effect of the exposure of cells to xenogeneic proteins during the isolation procedure and/or the culture period on autologous mixed lymphocyte reactions (AMLR) with non-T cells and phytohemagglutinin-activated T cells as stimulators was investigated. T and non-T cells were isolated by rosetting with 2-aminoethylisothiuronium bromide-treated sheep red blood cells (AET-SRBC), by nylon-wool filtration, and by positive or negative selection with anti-class II HLA antigens and anti-T-cell monoclonal antibodies. Isolation and cultures were performed in presence of fetal calf serum (FCS) or of autologous serum. In both types of AMLR, proliferation of responding cells did not require exposure to xenoantigens. However xenoantigens enhanced the proliferation of cells from some, although not all, the donors tested. There were differences in the degree of proliferation of the cells from the donors tested, but without correlation with the two types of AMLR. These results suggest that both types of AMLR reflect a self-recognition event and not a response to xenoantigens. However the potential interference of xenoantigens, as well as the individual variability, should be taken into account when interpreting the significance of abnormalities of AMLR in immunopathologic processes.
We studied the phenotype of T-lymphocytes isolated from 18 patients with head and neck cancer, their capacity to express Ia antigens upon activation by lectins in vitro, their capacity to function either as responder or stimulator cells in autologous mixed lymphocyte reaction, and their capacity to cooperate with the normal adherent suppressor cells (NASC). The T-lymphocytes isolated from these patients have several functional defects including an impaired capacity to activate allogeneic lymphocytes in mixed lymphocyte reactions (MLRs), a lack of a proliferative capacity in autologous MLRs, an impaired sensitivity to inhibition by NASC, and an impaired capacity to express Ia antigens upon activation by mitogens in vitro. These data indicate that, in patients with head and neck cancer, immune function is characterized by a defect in T-lymphocytes functions which concerns the process of cell to cell cooperation.
Six patients with Rheumatoid Arthritis (RA) have been treated with lymphocytapheresis after their disease proved unresponsive to conventional therapy. Clinical improvement, measured evaluating articular swelling, morning stiffness, and muscle weakness, was observed in four of the six patients. From the cellular point of view lymphocytapheresis induced (1) T cell depletion without modification of lymphocyte subsets in the peripheral blood, (2) improvement of lymphocyte responsiveness to lectins, autoantigens and alloantigens. All together these data suggest that therapeutic leukapheresis modifies the immune responsiveness in humans, possibly facilitating the process of cell to cell cooperation.