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Corticosensitivity influences the degree and the duration of an inflammatory reaction by altering target cell responses to endogenous and/or exogenous glucocorticoids. Indeed, different clinical responses to glucocorticoids have been observed among patients with Crohn's disease, suggesting different degrees of corticosensitivity in these subjects. The purpose of this study was to compare the corticosensitivity of patients with quiescent Crohn's disease to that of healthy subjects (HS). Nineteen patients with quiescent Crohn's disease and 14 HS were studied; all patients were steroid-free for at least six months; 7 of the 19 were corticosteroid-dependent (CSD) and treated with nonglucocorticoid immunosuppressants at the time of the study. Corticosensitivity was measured by the inhibition of LPS-induced cytokine secretion in whole blood cell cultures treated with increasing concentrations (10(-9) to 10(-6) M) of dexamethasone. Tumor-necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) were measured using specific immunoassays. Crohn's disease patients had a markedly decreased dexamethasone-mediated inhibition of TNF-alpha (P < 0.01), IL-6 (P < 0.001), and IL-1 beta (P < 0.01) compared to healthy subjects, with a shift of the dexamethasone dose-response curve to the right. No significant differences in the basal and LPS-stimulated secretion of the three cytokines were observed between CSD and non-CSD patients, and both subgroups of patients had similar degrees of dexamethasone-mediated cytokine inhibition. We conclude that patients with Crohn's disease have a significant decrease in the corticosensitivity of their leukocytes. This may be related to a specific genetic/constitutional background and/or could be acquired, due to inflammation-related endocrine and/or immune factors.

The thymic repertoire of neuroendocrine 'self' antigens has been previously described on the basis of the intrathymic expression of neurohypophysial (NHP)- and tachykinin-related peptide signals and receptors. According to that model, the cryptocrine signalling between thymic epithelial/nurse cells and thymocytes through NHP-related signals and receptors constitutes one accessory pathway in the process of T-cell differentiation and/or activation. A pharmacological manipulation of that novel type of cell-to-cell signalling was tested by the investigation of the immunomodulatory properties of novel cyclic hexapeptide oxytocin (OT) antagonists (MSD Research Laboratories). These compounds were found to significantly inhibit the productions of cytokines (mainly IL-1 beta and IL-6) elicited by anti-CD3 treatment of human whole blood cell cultures. Cytokine productions were more significantly reduced by OT antagonists in whole blood cell cultures derived from female volunteers than in those obtained from male donors, suggesting an influence of the gonadal steroid environment on the expression of NHP peptide receptors by immune cells. These observations support the concept of novel immunomodulating approaches through immune-specific neuropeptide antagonists, as well as the pharmacological value of such strategies in selective immunotherapy.

The preprotachykinin-A gene, the common gene of mRNAs encoding both substance-P (SP) and neurokinin-A (NKA), was shown to be expressed in Sprague-Dawley rat thymus by detection of specific mRNA in gel-blot analyses. In situ hybridization revealed dispersed PPT-A-labeled cells in sections from rat thymus, with a concentration of grains over a subpopulation of cells in the thymic medulla. Also, neuropeptide-Y mRNA-expressing cells were found in the rat thymus, primarily in the thymic medulla. Rat thymic extracts contained SP-like immunoreactivity (SP-LI), and the major part of the immunoreactivity coeluted with authentic SP and SP sulfoxide standards. SP-LI was also detected in human thymus, which contained between 0.09-0.88 ng SP-LI/g wet wt. Evidence for translation of preprotachykinin-A mRNA in the rat thymus was obtained from the demonstration of NKA-LI in thymic cells with an epithelial-like cell morphology. Combined with previous observations on the immunoregulatory roles of tachykinin peptides and the existence of specific receptors on immunocompetent cells, the demonstration of intrathymic synthesis of NKA suggests a role for NKA-LI peptides in T-cell differentiation in the thymus.

5 micrograms of human beta-endorphin were labelled with 2 mCi 125I by the chloramine T technique. After two gel filtrations on Sephadex G-15 and on Sephadex G-50 in phosphate buffer with EDTA, Trasylol and mercapto-ethanol, a pure tracer was obtained with a specific activity about 150 microCi/ug. Kept at + 4 degrees C, the tracer remained utilizable for 30 days without loss of immunoreactivity. The labelling with lactoperoxydase and the use of another gel filtration method (filtration on Aca 202) gave a 125I beta-END tracer with the same immunoreactivity. The binding of this tracer to the antibody of an anti-beta-END antiserum diluted at 1/8000 was 32% with a non specific binding of 2%. 5 micrograms of human beta-lipotropin were labelled with 0.5 mCi 125I by the lactoperoxydase method. After two gel filtrations on Sephadex G-25 and on Sephadex G-75 in phosphate buffer with EDTA, Trasylol and mercapto-ethanol, a pure tracer with a specific activity of 140 microCi/micrograms was obtained. It remained utilizable for 30 days when kept at + 4 degrees C. Gel filtration on Aca 202 did not give good purification, while gel filtration on Aca 54 was good but slower than on Sephadex G-75. The binding to antibody in absence of unlabelled beta-LPH was 32% for an anti-beta-LPH antiserum diluted at 1/4000. The non specific binding was 2.5%.

Using specific homologous radioimmunoassays of native hCG and its alpha and beta subunits, we determined the levels of these glycoproteins in unfiltered maternal blood serially obtained in five non-invasive hydatidiform moles before and after evacuation. Some of these samples were assayed after gel filtration chromatography on Sephadex G 100. Twelve samples, obtained in cases of invasive trophoblastic tumour after ablative surgery and chemotherapy, were also assessed for their hCG, hCG alpha and hCG beta content. In unaborted moles, mean circulating levels of native hCG and free hCG beta were considerably increased (seven and thirteen times, respectively) as compared to normal pregnancies of the same age, whereas levels of free hCG alpha were either normal or slightly elevated. Chromatographic analyses of molar sera confirmed the presence of free circulating subunits, and separated hCG beta in its monomeric form from its higher molecular weight form, the latter being in greater quantity than in normal pregnancy sera. In contrast, the elution profile of serum native hCG was comparable in cases of normal and molar pregnancy. Successful curettage was accompanied by a return to normal levels of the native hCG and its alpha and beta subunits in 40-90 days. Persistence of tumour tissue was indicated by a slight increase in levels of native hCG and the beta subunit. Determination of alpha subunit level was less useful for the detection of any relapse.

Homologous radioimmunoassays have been developed for native hCG and its alpha and beta subunits. Their specificities were assessed by analysis of the inhibition ca and beta subunits. 1. During normal singleton and twin pregnancies.

Several substances, referred to as tumor markers, are associated with neoplasms development. The specificity of these cancer related substances or antigens depends on their nature (onco-fetal antigens, placental antigens) or on their concentration and physico-chemical forms (hormones, exocrine products, enzymes,...). On the basis of physico-chemical, immunochemical and biochemical analogies which exist between these tumor markers and substances normally found at particular times of life, a classification of these markers may be proposed. Tumor markers are almost constantly found within carcinoma cells by immunocytochemical techniques and are secreted by carcinoma explants in culture medium. On the hand, the release of tumor markers in biological fluids (blood, cerebrospinal fluid, urines,...) is less frequently detected by sensitive methods such as radioimmunoassay. Several factors are responsible for this discrepancy between the intra-tumoral presence of tumor markers and the lower incidence of their detection in biological fluids. These factors are discussed. These tumor markers have attracted considerable attention from pathologists and clinicians. Thus, detection of these substances, especially by immunocytochemical methods, may be related to a situation of neoplastic transformation and allow a functional classification superimposed to histological classification superimposed to histological classification of tumors. Moreover, ectopic production of hormones and/or neuromediators explains some clinical symptoms in cancer processes. Furthermore, products of normal cell activity at the origin of cancer (hormones, enzymes, exocrine products) when evidenced within the neoplastic cells or within serum might constitute a hormonal dependence index useful for therapeutical orientation. Finally, tumor marker levels are related to the local and systemic extension of the neoplasia and may be considered as valid index of prognosis. The determination of the levels of these tumor markers provides a quantitative criterion of the evolution of the neoplastic disorder and for following the efficacy or inefficacy of treatment.

Using a radioimmunoassay for human leukocyte interferon (IFN alpha), pharmacokinetic studies were carried out in twelve cancer patients given sequential intramuscular injections of Hu IFN alpha 2. Even though individual monitoring of serum IFN titers emphasized, for a given dose, marked quantitative variations of the observed maximum concentrations, their mean values were found to be dose-dependent (358 +/- 167 U/ml at 30.10(6) U and 1044 +/- 599 U/ml at 100.10(6) U doses). Comparison with bioassay results showed that IFN activities measured in sera were of the same order of magnitude as those calculated from radioimmunoassay standard curves. Data obtained from this series on observed peak time, half-life value and serum concentrations were consistent with those reported by the other groups using recombinant leukocyte interferon in clinical trial. Therefore, radioimmunoassay is an useful method for routinely assaying IFN alpha used either as antitumour or antivirus agent because of its high sensitivity (4 U/ml) and its simplicity.

A radioimmunoassay for human interferon gamma (IFN-gamma) has been carried out using a recombinant glycosylated interferon (Hu IFN-gamma) as tracer, the N.I.H. reference preparation (Gg 23-901-530) and a polyclonal rabbit antiserum. The assay is highly specific for IFN-gamma: there is no cross-reaction either with interferons alpha and beta, Interleukins 1 and 2, tumor necrosis factor alpha and beta or with various brain peptides. The sequential saturation procedure allowed a sensitivity of 0.4 U/ml with intra and between assay coefficients of variation less than 8 and 12%, respectively. The in-vitro production of IFN-gamma by peripheral blood mononuclear cells (P.B.M.C.) was also measured. In unstimulated cultures, IFN-gamma production remained undetectable, i.e. below the 0.4 U/ml sensitivity level. After stimulation of P.B.M.C. from normal subjects with increasing amounts of PHA, both the 3H-thymidine incorporation and IFN-gamma release followed bell-shaped curves. There was no significant difference of 3H-thymidine incorporation between PHA stimulated cultures (0.2 and 2.5 ug/ml) from normal subjects (36 cases) and those with active (16 cases) or non-active (14 cases) rheumatoid arthritis. At two PHA concentrations of 0.2 and 2.5 ug/ml, mononuclear cells from patients with active disease produced significantly less IFN-gamma than those from either controls or cases with non-active disease.

Homologous radioimmunoassay of human prolactin was performed and used to investigate the secretion of this pituitary hormone under normal and pathological conditions. The following data were developed in this paper: --During the menstrual cycle, prolactin levels are more elevated during ovulatory and luteal phases than during follicular phase; --During pregnancy, prolactin levels progressively increase to reach their maximum at the end of gestation; --During lactation, prolactin levels increase for the two days following delivery, then progressively decrease; --Bromocryptine oral administration drastically reduces prolactin levels within the 24 hours as it inhibits the prolactin release normally induced by suckling. Assays of prolactin is useful to define the role of this hormone in the genesis of the galactorrhea. Bromocryptine as L Dopa reduce the hyperprolactinemia either functional or tumoral in origin. TRH provokes prolactin release which is more pronounced in females than in males. Pituitary prolactin reserve may be appreciated in several pathological conditions. It appears to be of first interest to assess the residual function of the pituitary gland after surgical removal of adenoma. Depuis 1971, la prolactine humaine peut être dosée dans les milieux biologiques par méthode radio-immunologique (G. BRYANT et coll., 1971; M. L'HERMITTE et coll., 1972; H. FRIESEN et coll., 1972; SINHA et coll., 1973). En 1974 nous avons proposé une méthode de dosage radio-immunologique homologue (A. REUTER et coll., 1976). Grâce à celle-ci nous avons exploré la sécrétion de cette hormone hypophysaire dans certaines conditions normales et pathologiques.

A radio-immunoassay for human T cell growth factor, also called Interleukin-2 (IL-2), has been carried out using a recombinant IL-2 preparation as tracer and a polyclonal rabbit antiserum. The assay is highly specific for IL-2: there is no cross-reaction with either type I and II interferons, epidermal growth factor or tumor necrosis factor alpha. Using the sequential saturation procedure the limit of sensitivity was 0.5 U/ml. Intra- and between-assay coefficients of variation were 8 and 11%, respectively. With this assay, IL-2 recovery in serum and peripheral blood mononuclear cell culture (P.B.M.C.) medium was 79 and 95%, respectively. In serum of 109 normal subjects and 102 rheumatoid arthritis patients mean IL-2 concentrations (+/- SD) were 1.5 +/- 0.5 U/ml and 1.4 +/- 0.4 U/ml respectively. The IL-2 production by P.B.M.C. in vitro was also studied. In unstimulated cultures, IL-2 release remained undetectable, i.e. below 0.5 U/ml. After stimulation of mononuclear cells from 36 normal subjects with increasing amounts of phytohemagglutinin (PHA), the 3H-thymidine incorporation followed a bell-shaped curve, the maximum response being observed at a 2.5 micrograms/ml PHA concentration. After a 72-hr mononuclear cell stimulation, IL-2 release increases with PHA concentrations ranging from 0 to 10 micrograms/ml. In patients with rheumatoid arthritis (R.A.), P.B.M.C. incorporated 3H-thymidine as in normal subjects. In contrast, mean +/- SEM IL-2 production by P.B.M.C. from patients with inactive RA (5 +/- 0.9) and active disease (1 +/- 0.5) was significantly lower than that from normal subjects (12 +/- 0.7 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)