Hyperprolactinemia inhibits natural killer (NK) cell functionin vivo and its bromocriptine treatment not only corrects it but makes it more efficient

We studied NK cell function in eight patients with pathological hyperprolactinemia by measuring⁵¹Cr release by K562 cells exposed to their mononuclear cells and found it decreased compared to normal controls (P<0.01). Bromocriptine (BrC) treatment corrected NK function but also made it more efficient at 12:1 than at 25:1 or 50:1 effector:target ratios (ANOVA;P=0.01). The study of NK cell function in agarose revealed that its decrease in hyperprolactinemia is due to their low active binding to target cells, active killing, and recycling capacity. BrC tended to correct them but also increased recycling capacity to levels higher than those of controls (P<0.05). Sequential studies in three hyperprolactinemic patients before and after BrC showed correction of NK function within 1 week but its increased efficiency at the 12:1 effector:target ratio required 8 weeks. We conclude that hyperprolactinemia decreases NK cell function. BrC corrects this by decreasing prolactin levels but also makes NK function more efficient by increasing the capacity of NK cells to recycle after killing.     

Influence of dose and route of Mycobacterium lepraemurium inoculation on the production of interleukin 1 and interleukin 2 in C57BL/6 mice

Groups of C57BL/6 mice were infected either intravenously or subcutaneously with 10(5) or 10(8) Mycobacterium lepraemurium cells, and the ability of their splenic macrophages and T-cells to produce, respectively, interleukin 1 on lipopolysaccharide stimulation and interleukin 2 on concanavalin A stimulation was assessed during the course of infection. In all groups of infected mice, interleukin 1 production remained unaffected during the entire observation period, whereas interleukin 2 activity decreased as the infection progressed. Heavily infected mice (10(8) M. lepraemurium cells) showed an earlier and stronger deficiency interleukin 2 production by concanavalin A-stimulated spleen cells than did mice infected with a lower dose (10(5) bacilli), without detectable influence by the route of inoculation. In mice receiving 10(5) bacilli, minor differences were seen according to the route of infection, with a slight delay in interleukin 2 decrease in mice injected intravenously. In subcutaneously inoculated mice, the failure of spleen cells to produce interleukin 2 after concanavalin A stimulation did not correlate with the number of bacilli developing in the spleen, suggesting the existence of suppressor mechanisms acting at a distance from the site of inoculation.     

Defective gamma-interferon production in peripheral blood leukocytes of patients with acute tuberculosis

Production of interferon (IFN)-gamma by peripheral blood leukocytes (PBL) was examined in cultures of unseparated fresh whole blood exposed to phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM). The yield of IFN-gamma was measured by a newly developed immunoradiometric assay. Nine of 14 patients with acute pulmonary tuberculosis (TB) showed a depressed IFN-gamma response to Con A and/or PWM. Only four of these TB patients also showed a depressed IFN-gamma response to PHA. Stimulation of the patients' PBL cultures with PHA in the presence of exogenous interleukin 2 (IL 2) produced normal IFN-gamma yields in all but the most severely depressed patients. PBL cultures of TB patients with defective IFN-gamma production in response to mitogenic lectins also produced less IFN-gamma after stimulation with tuberculin PPD. Although some patients showed a moderate degree of lymphopenia, their OKT4/T8 lymphocyte ratios were mostly normal or close to normal, with the notable exception of one TB patient who has been diagnosed to have the acquired immune deficiency syndrome (AIDS).     

Cell-mediated immunity and biological response modifiers in insulin-dependent diabetes mellitus complicated by end-stage renal disease

Previous studies have shown several immunoregulatory abnormalities in insulin-dependent diabetes mellitus (IDDM). In this report we compared peripheral blood mononuclear cells (PBMC) from patients with IDDM complicated by end-stage renal disease (ESRD) to those from normal subjects and from patients with ESRD of different etiologies for their: natural killer (NK) and antibody-dependent cell-mediated cytotoxic (ADCC) activities; modulation of NK and ADCC activities by biological response modifiers (BRM) including purified human lymphoblastoid interferon, human recombinant alpha-2 interferon, human gamma interferon and human recombinant interleukin 2; proliferative response of T and B lymphocytes to concanavalin A (Con A), phytohemagglutinin and pokeweed mitogen, and ability to produce T-cell growth factor (interleukin 2; IL-2). PBMC of diabetic patients demonstrated significantly lower NK activity than normal and ESRD subjects. Upon treatment with BRM, NK activity was augmented and achieved normal levels. ADCC activity was not different from that of normal controls and exhibited similar increases when stimulated by BRM. The proliferative responses to Con A, phytohemagglutinin and pokeweed mitogen as well as IL-2 production in response to Con A stimulation were significantly lower in the IDDM group. Our results indicated that NK cells from patients with IDDM can respond to IL-2 with enhanced cytotoxicity, and, because activation of resting T cells by mitogenic stimuli depends on the production of IL-2 as well as the appearance of a receptor for IL-2, our finding of low levels of in vitro IL-2 production by PBMC from patients with IDDM may explain the depressed NK activity and the observed poor response to T-cell mitogens.     

利培酮、氟哌啶醇对血浆泌乳素影响及其与疗效的关系

目的：研究典型、非典型抗精神病药对精神分裂症患者血浆泌乳素（ＰＲＬ）水平的影响及其与疗效的关系。方法：选择符合ＩＣＤ－１０和ＣＣＭＣ－２－Ｒ诊断标准的精神分裂症患者,按双盲、随机法分为利培酮组和氟哌醇组,治疗１２周。采用阳性和生症状量表（ＰＡＳＳ）在治疗前后分别评定一次;用放射免疫法在治疗前后 浆ＰＲＬ浓度。结果：有、后两组在ＰＡＮＳＳ 发及其因子分上均无显著差异,但部酮组症状改善者明显多于氟哌啶     

The effect of piroxicam on interleukin production and responsiveness in patients with ankylosing spondylitis

Interleukin (IL) production and responsiveness of peripheral blood lymphocytes (PBL) from 10 patients with ankylosing spondylitis (AS) were compared with that of 15 age-matched control subjects. Patients discontinued all antiinflammatory medication seven days prior to testing. After the initial assessment, piroxicam 20 mg daily was given to five patients for 30 days and the studies repeated. Interleukin was generated by the addition of staphylococcal protein A (SpA) to serum-free microcultures of PBL. 48-hour culture supernatants were assayed for interleukin by determining their capacity to induce mouse thymocyte proliferation in the presence of a suboptimal dose of concanavalin A. Interleukin activity was quantified by profit analysis of enhanced³H-thymidine uptake. Normal resting PBL are unable to respond to IL-2 without prior activation. Thus responsiveness to interleukin was determined by culturing PBL for 48 hours with or without SpA and exposing the cells to an internal laboratory interleukin standard.³H-thymidine uptake was measured after a further 4 days.The production of interleukin by PBL from AS patients (23.9±6.0 IL units/ ml) was comparable with that from control subjects (23.4±8.9 units/ml). Interleukin generation in the five patients given oral piroxicam was similar before (27.0±6.2 units/ml) and after therapy (23.6±9.3 units/ml). Also similar were the minimal responsiveness to exogenous interleukin of resting PBL from controls as well as AS patients pre- and post-piroxicam therapy. This last observation is in contrast with previous data from patients with recently active rheumatoid arthritis whose PBL were responsive to exogenous interleukin even without prior mitogenic stimulation. When cultures were pre-activated with SpA before being exposed to interleukin, PBL from untreated AS patients showed enhanced responsiveness to exogenous interleukin (mean cpm 183,000±95,472) when compared with control subjects (mean cpm 97,914±96,232). This difference was not statistically significant. However, following piroxicam therapy in four of five patients, the enhanced responsiveness was partially reversed towards normal (mean cpm 251,360±73,382 to 170,300±69,237). Further studies on the effect of piroxicam in prostaglandin mediated enhanced proliferation of PBL to mitogens or interleukin may be fruitful.     

Suppressor factor of T-cell activation and decreased interleukin 2 activity in experimental African trypanosomiasis.

Spleen cells from Trypanosoma brucei-infected BALB/c mice were unable to respond to a T-cell mitogen, concanavalin A. Moreover, they were unable to produce detectable amounts of the growth factor required for T cell proliferation, interleukin 2. In addition, supernatants from 24-h in vitro cultures of these cells produced a slight but detectable suppressive activity of the interleukin 2-dependent proliferation of a T-cell line. Infected spleen cells also suppressed the response of T. brucei-immunized spleen cells as well as normal spleen cells to concanavalin A. However, a major difference was shown in the mechanism of the suppression in both systems. Suppression of normal spleen cells required cell-to-cell contact. In contrast, suppression of 30-day T. brucei-immune cells could be mediated by a soluble suppressor factor released by in vitro culture of infected spleen cells. This molecule had an apparent molecular weight of 18,000. Finally, similar suppression could be generated in 30-day T. brucei-immune spleen cells but not in normal cells, with living cells but not with extracts of T. brucei.     

本草九代对慢性迁延性肝炎患者血清可溶性白细胞介素2受体水平的调节作用

用ELISA方法检测了29名慢性迁延性肝炎患者和18名健康献血员血清可溶性白细胞介素2受体(sIL-2R)水平,同时进行了血清IL-2与sIL-2R的相关分析。结果发现,正常人sIL-R为147±72.1u/ml,而慢性迁延性肝炎病人sIL-2R显著升高(210.5±84).GWe治疗3个月后sIL-2水平显著下降(185.8±79);同时发现IL-2水平与sIL-2R 有一定相关性。上述结果提示GWe具有调节机体IL-2功能的独特作用。     

Impaired Mitogen-Induced Interferon-γ Production in Rheumatoid Arthritis and Related Diseases

Peripheral blood lymphocytes from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS), Reiter's disease, osteoarthritis, and from healthy volunteers were investigated for interferon-gamma (IFN-gamma) production after mitogen activation. Phytohaemagglutinin stimulation revealed an impaired IFN-gamma production in RA, SLE, and PSS but normal levels in Reiter's disease and osteoarthritis. In RA this deficiency was also seen after pokeweed mitogen, OKT3, and concanavalin A activation. No major differences were found in interleukin 2 (IL-2) production and cell proliferation. The IL-2 receptor expression was reduced on stimulated RA lymphocytes. The deficient IFN-gamma production was compensated in RA by co-stimulation of PHA or OKT3 with phorbol myristic acetate (PMA). In addition, the combination of the calcium ionophore A 23187 and PMA induced a strong IFN-gamma secretion in all patient groups and in the controls.     

Kinetics of lymphoproliferative responses following scald injury in a rat burn model

Splenic lymphocytes from scalded and nonscalded rats were studied for their proliferative response to phytohemagglutinin, and to allogeneic cells in a one-way mixed lymphocyte culture (MLC). A significant suppression of the proliferation of lymphocytes in both these assays was observed as early as 4 days postinjury as measured by the [3H]thymidine uptake studies. The lymphocyte response to PHA returned to normal levels by Day 21 postinjury, whereas the MLC responses continued to be suppressed. The MLC responses between nonburned and burned animals could be restored by the addition of a lymphokine-rich culture supernatant obtained from concanavalin A-activated lymphocytes from normal nonburned rats, as well as by the addition of purified human interleukin 2 (IL-2) and rat interleukin 2. However, the addition of purified human interleukin 1 and human interferon gamma (Hu-IFN-gamma) did not bring about a significant change in the proliferation of burned rat spleen cells in MLC. Cells from burned rats were also tested for the development of suppressive activity by adding splenic lymphocytes from 2-week postburn rats to an ongoing one-way MLC. The addition of lymphocytes from burned rats resulted in significant suppression (81%) of MLC responses among normal nonburned rats. The data suggest that the development of suppressor cells following burn injury along with a defect in production and/or uptake of IL-2 may be partly responsible for immune suppression following burn injury. Since the proliferative response of lymphocytes from thermally injured rats is suppressed in a similar fashion as that found in thermally injured patients, the rat appears to be a good model for the study of kinetics of immune suppression following burn injury.     

Cytokine Production in Cell Culture by Peripheral Blood Mononuclear Cells from Immunocompetent Hosts

The production of interleukin 2 (IL-2) gamma interferon, IL-4, tumor necrosis factor alpha (TNF-α), TNF-β, IL-5, and IL-10 in vitro by peripheral blood mononuclear cells cultured from healthy immunocompetent subjects after mitogen stimulation was determined. The mitogens used were concanavalin A, phytohemagglutinin, pokeweed mitogen, and Staphylococcus aureus Cowen. The results obtained provide a normal range for the production of these cytokines under specified conditions in vitro.     

T-Cell Abnormalities in Antibody Deficiency Syndromes

We studied two patients with hypogammaglobulinaemia, three with selective IgA deficiency, and four with selective extreme IgM deficiency for T-cell abnormalities in the circulating blood. Most patients had altered CD4+ helper/inducer and CD8+ suppressor/cytotoxic T-cell subsets, and an elevated percentage of HLA-DR+ and interleukin 2 (IL-2) receptor+ antigens on lymphocytes. One patient with the selective IgA deficiency had an absence of CD4+ T cells in blood. The lymphocytes of eight patients showed a diminished proliferative response and deficient IL-2 production in response to stimulation with phytohaemagglutinin or concanavalin A. The three patients with selective IgM deficiency were found to have a defective T-cell abnormality in IgM synthesis by B cells. It is interesting that CD8+ T cells of the two patients with IgM deficiency demonstrated suppressor cell function for IgM synthesis by the normal B and T cells.     

Interleukin 2 deficiencies in rheumatoid arthritis and systemic lupus erythematosus

The ability of peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren's syndrome (SS) to produce interleukin 2 (IL-2) and respond to it in-vitro was examined. Phytohemagglutinin-stimulated lymphocytes from over half of the SLE patients exhibited a decreased ability to produce IL-2 while their concanavalin A-generated blast cells responded normally to exogenous IL-2. Lymphocytes from RA patients not only produced less IL-2 than normals (P less than 0.001), but also responded poorly to exogenous IL-2 (P = 0.011). These abnormalities did not correlate with the patient's age, sex, duration of disease, or disease activity. Production of and response to IL-2 was widely varied among patients with SS and not different from controls. The decreased response of RA lymphocytes to IL-2 may result from a smaller number of cell surface IL-2 receptors since IL-2 adsorption to RA cells was lower than to either SLE or normal cells. These data suggest that IL-2-related abnormalities may play a role in the disordered immunoregulation characteristic of RA and perhaps of SLE.     

Functional Properties of Neoplastic T Cells in Helper T Cell Prolymphocytic Leukaemia with IgM Hypergammaglobulinaemia

A case of T cell prolymphocytic leukaemia of helper/inducer T cell phenotype with IgM hypergammaglobulinaemia in a 65-year-old Saudi man is presented. The neoplastic T cells in the patient had an OKT3+, OKT4+, OKT8-, OKT11+, OKCLL+, OKIa1+, OKDR+, Tac+ phenotype. The presence of OKIa1+, OKDR+, and Tac+ antigens indicates that the leukaemic T cells were in an activated state. The cells responded to phytohaemagglutinin, but showed a diminished response to concanavalin A. The reduced interleukin 2 receptor expression and interleukin 2 production were associated with defective concanavalin A-induced proliferation. There was suppression of mixed lymphocyte culture reaction between the patient and two healthy donors in response to concanavalin A. In vitro immunoglobulin production experiments demonstrate that the leukaemic T cells provided an enhanced helper cell function to produce IgM, and suppressor cell function to produce IgG immunoglobulins by pokeweed mitogen-induced normal B lymphocyte differentiation. In this study we also found that the patient's T cells proliferate in response to lipopolysaccharides, thus providing the first evidence that leukaemic (OKT4+) T cells from a prolymphocytic leukaemia patient can be stimulated by lipopolysaccharides.     

Normal development of lymphokine activated killing (LAK) in peripheral blood lymphocytes from hyperprolactinemic patients.

The effect of prolactin on the interleukin 2 (IL2)-driven development of Lymphokine Activated Killing (LAK) by normal PBL and by PBL from hyperprolactinemic patients was investigated. Concentrations of PRL corresponding to the physiological serum levels of the hormone and to the Kd of the PRL receptors on NK cells (6-20 ng/ml, 0.3-1 nM) had no effect on the generation of LAK activity by normal PBL, whereas 100-200 ng/ml were slightly, although significantly, inhibitory. By contrast, PBL from 16 hyperprolactinemic patients developed levels of LAK activity comparable with those generated by PBL from age- and sex-matched normoprolactinemic donors.     

Efficacy and Safety of Cabergoline as First Line Treatment for Invasive Giant Prolactinoma

Although cabergoline is effective in the treatment of micro- and macro-prolactinoma, little is known about its efficacy in the treatment of invasive giant prolactinoma. We investigated the efficacy and safety of cabergoline in 10 male patients with invasive giant prolactinoma. Before treatment, mean serum prolactin level was 11,426 ng/mL (range, 1,450-33,200 ng/mL) and mean maximum tumor diameter was 51 mm (range, 40-77 mm). Three months after initiation of cabergoline treatment, serum prolactin concentrations decreased more than 97% in 9 patients; at last follow-up (mean treatment duration, 19 months), the mean decrease in serum prolactin concentrations was 98%, with 5 patients having normal serum prolactin levels. At first MRI follow-up (3-12 months after initiation of cabergoline), the mean reduction in tumor size was 85±4% (range, 57-98%). Cabergoline treatment for more than 12 months caused a greater reduction in tumor size compared to the treatment for less than 12 months (97±1% vs. 78±7%, P<0.05). These findings indicate that cabergoline treatment led to a significant and rapid reduction in serum prolactin concentrations and tumor size in patients with giant prolactinoma. Therefore, cabergoline represents an effective and well-tolerated treatment for invasive giant prolactinoma.     

Absence of prolactin gene expression in colorectal cancer.

AIMS: Previous studies documenting hyperprolactinaemia in patients with colorectal cancer have suggested that the tumour is the source of hormone production. The aim of this study was to determine the frequency of hyperprolactinaemia in patients with colorectal cancer before, during, and after surgery, and also to determine whether prolactin is produced by these tumours. METHODS: Serum prolactin concentrations were measured in 20 patients with colorectal cancer before, during, and after surgical resection of their tumours. Samples taken during surgery included peripheral venous blood and blood taken from the main veins draining the tumour. To determine whether the tumour was responsible for the production of prolactin in these patients, paraffin wax embedded sections of tumour specimens were subjected to immunohistochemistry and western blotting using a monoclonal antibody to prolactin. RESULTS: Five patients (three women, two men) had preoperative prolactin concentrations above the normal reference range, although this increase was of clinical importance in only two. After surgical resection of their tumours, prolactin concentrations remained high in both patients. All 20 patients had greatly raised prolactin values at the time of surgery, irrespective of whether this was measured in peripheral blood or in blood taken from veins draining the tumour. All 20 colorectal cancer tissue samples, including those with raised preoperative and/or postoperative prolactin concentrations, were negative for prolactin staining. Frozen tissue was also available in four cases. The absence of prolactin gene expression in these four tumours was confirmed both by repeat immunohistochemistry and by western blotting. A further 50 colorectal cancer cases examined by immunohistochemistry alone were also unreactive for prolactin. CONCLUSIONS: The results of this study suggest that serum prolactin concentrations may occasionally be raised in colorectal cancer patients, but that the tumour is not the source of hormone production.     

Effect of vitamin E therapy on sexual functions of uremic patients in hemodialysis.

Twenty-four uremic patients on hemodialysis who had never been treated with vitamin E or related drugs and 12 control patients with normal renal function were studied. Hemodialysis patients were randomly divided into two groups; 12 were treated with oral vitamin E (300 mg/day) for eight weeks and 12 uremic patients and 12 controls were given placebo. Serum vitamin E, prolactin, FSH, LH, and free testosterone levels were measured in all patients before and after treatment. After the vitamin E treatment serum prolactin levels were significantly decreased (50.8 vs 15.4 ng/ml, p < 0.01). Vitamin E levels were significantly increased (1.11 vs 1.22 mg/dl, p < 0.05). Serum FSH, LH and free testosterone were not affected. In the other two groups there were no significant changes. These results show that vitamin E treatment lowers prolactin levels in uremic hemodialysis patients. This might be due to inhibition of central prolactin secretion. Vitamin E inhibits pituitary gland hypertrophy in vitamin E-deficient rats.     

Absence of prolactin gene expression in colorectal cancer.

AIMS: Previous studies documenting hyperprolactinaemia in patients with colorectal cancer have suggested that the tumour is the source of hormone production. The aim of this study was to determine the frequency of hyperprolactinaemia in patients with colorectal cancer before, during, and after surgery, and also to determine whether prolactin is produced by these tumours. METHODS: Serum prolactin concentrations were measured in 20 patients with colorectal cancer before, during, and after surgical resection of their tumours. Samples taken during surgery included peripheral venous blood and blood taken from the main veins draining the tumour. To determine whether the tumour was responsible for the production of prolactin in these patients, paraffin wax embedded sections of tumour specimens were subjected to immunohistochemistry and western blotting using a monoclonal antibody to prolactin. RESULTS: Five patients (three women, two men) had preoperative prolactin concentrations above the normal reference range, although this increase was of clinical importance in only two. After surgical resection of their tumours, prolactin concentrations remained high in both patients. All 20 patients had greatly raised prolactin values at the time of surgery, irrespective of whether this was measured in peripheral blood or in blood taken from veins draining the tumour. All 20 colorectal cancer tissue samples, including those with raised preoperative and/or postoperative prolactin concentrations, were negative for prolactin staining. Frozen tissue was also available in four cases. The absence of prolactin gene expression in these four tumours was confirmed both by repeat immunohistochemistry and by western blotting. A further 50 colorectal cancer cases examined by immunohistochemistry alone were also unreactive for prolactin. CONCLUSIONS: The results of this study suggest that serum prolactin concentrations may occasionally be raised in colorectal cancer patients, but that the tumour is not the source of hormone production.     

Endocrinology: Serum pattern of different molecular forms of prolactin during normal human pregnancy

In this study, the molecular heterogeneity of prolactin wasanalysed in serum from normal women throughout pregnancy. Lectinaffinity chromatography and denaturing polyacrylamide gel electrophoresisunder reducing and non-reducing conditions, followed by Westernblotting and immunostaining were used to resolve and identifythe molecular variants of prolactin. During the first trimester,large molecular forms (64 and 53 kDa) and those correspondingto glycosylated and non-glycosylated prolactin (25 and 23 kDa,respectively) were present either under reducing or non-reducingconditions. The 64 and 23 kDa were the predominant species atthis stage of gestation. As pregnancy progressed, the 64 kDavariant, which did not bind to con-canavalin A, decreased untildisappeared at the third trimester of gestation. The unbound/boundratio of serum prolactin to concanavalin A increased only atthe third trimester; however, the relative proportions of concanavalinA-bound prolactin did not show statistically significant changesalong the gestational period. The results demonstrated the occurrenceof changes in the heterogeneity of prolactin during gestationand further confirmed previous observations that various formsof non-glycosylated prolactin are indeed the predominant speciesin serum from normal women throughout pregnancy.