We investigated the in vitro effect of domperidone-induced hyperprolactinemia on plasma cytokine concentration and blood leukocyte cytokine production in healthy female volunteers. No changes were found in the plasma concentration of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-10, IL-6 and IL-13 during hyperprolactinemia when compared with control values. Using unseparated blood leukocytes, we found that the spontaneous production of IL-6 (4-8 h) and transforming growth factor (TGF)-beta 1 (2-4 h) was significantly decreased and that the in vitro stimulated production of IFN-gamma (2-8 h) and TNF (4 h) was significantly increased compared with control. Our data concerning the increased IFN-gamma and TNF producing capacity of unseparated leukocytes during pharmacologically induced hyperprolactinemia strongly support the possibility that the lymphocyte production of these cytokines can be rapidly amplified by prolactin via a priming mechanism.

Vermiculine, a macrocyclic aglycosidic dilactone isolated from Penicillium vermiculatum, was shown to have an inhibitory effect on the ability of concanavalin A to induce cytokine production in unseparated peripheral blood leukocytes (whole blood cultures). Vermiculine inhibited the production of (FN-gamma > IL-2 > TNF > IL-6. However ils effect on IFN-gamma and IL-2 was found to be bimodal. The suppressive effect of vermiculine was manifested at low concentrations (0.01 to 1.0 mu g/ml) of the agent and an increased production of cytokines was observed when the highest concentration of the agent (10 mu g/ml) was used. Vermiculine suppression of IFN-gamma production by unseparated leukocytes from healthy donors and from patients with rheumatoid arthritis exhibited a difference of about 2 to 20%.

After oral administration of a combination of hydrolytic enzymes (Wobenzym(R)) the leukocyte system of healthy subjects and patients with rheumatoid arthritis (RA) responds to ConA and NDV in vitro through a different pattern of IFN-gamma and IFN-alpha production, respectively in healthy subjects, after Wobenzym(R) medication the IFN-gamma as well as the IFN-alpha producing ability was increased. This cell system was not able to release a detectable level of IFN-gamma spontaneously and trypsin itself had no IFN-inducing ability. RA patients with defi cient producing ability of leukocytes to ConA failed to be restored in IFN producing capacity by the enzyme preparation and were even more decreased in the production of IFN-gamma after enzyme treatment. Wobenzym(R) treatment of healthy volunteers reduced TGF-beta 1 concentration in their plasma. in contrast to these results, whole blood cells of these volunteers produced TGF-beta 1 spontaneously.

Domperidone, anti-emetic drug, given to healthy female volunteers, induced an elevation of plasma prolactin (PRL) concentration with the peak in 1-4 h. The release of prolactin had a transient stimulating effect on theophylline sensitive T lymphocytes and on concanavalin A induced mitogenic activity, suggesting an enhanced activity of T suppressor lymphocytes. The relative number of CD4+ lymphocytes decreased markedly one hour after domperidone administration and returned to normal values within 2 h (that means 3 h after taking the drug). The number of lymphocytes positive for dipeptidyl peptidase IV exhibited similar transient increase and normalization of activity. No change was observed in the number of CD8+ lymphocytes. The production of interferon by leukocytes treated with Newcastle disease virus was found to be significantly increased 2 h after domperidone administration. The results suggest that prolactin can selectively stimulate some functions of cellular immunity as well as the release of cytokines (IFN). The present study may contribute to the understanding of the role of the immune system in endogenous hyperprolactinemia.

The authors review recent findings pertaining to the pathogenesis of systemic lupus erythematosus. It was revealed that knowledge of impaired humoral and cellular immunity is of great practical importance and substantially improves the prognosis of the disease.

The presence of an acid- and thermolabile IFN∝was repeatedly reported both in autoimmune diseases /including AIDS/ and in non-processed preparations of human leukocyte IFN. In an attempt to characterize this IFN, we used monoclonal antibodies obtained from hybridomas after immunization of BALB/c mice with a high titered non-processed leukocyte IFN preparation. These antibodies showed high selectivity for the acid- and thermolabile IFN∝. They did not react with the acid-and thermostable IFN∝ or other IFN types. However, antibodies against acid-labile and acid-stable IFN∝ both could be occasionally found in polyclonal anti-IFN sera and, rarely, also in monoclonal antibody preparations against unrelated IFN gamma and other types. This suggests that the acid-labile IFN alpha in normal leukocyte IFN preparations may represent new IFN∝ subspecies, or, a hitherto unknown cell inhibitor.

Macrophage (MO) and natural killer (NK) cell mediated cytotoxicity to K562 target cells were strikingly decreased in patients with systemic lupus erythematosus (SLE). SLE NK cells failed to release soluble factor(s) for lysing the targets. IFN-induced enhancement of both types of cytotoxicity was impaired. NK cells from healthy subjects kept their activity in culture with or without IFN for more than six days whereas SLE NK cell activity declined to zero at day 3. So, the increased IFN level of many SLE patients and a possible prior IFN priming effect seemed unrelated to the insensitivity to exogenous IFN in vitro. Inhibition factor(s) of SLE serum suppressed NK cytotoxicity in the presence of IFN whereas IFN sensitivity of MO remained unaffected indicating the complex regulation by serum components of immune reactions.

An acid- and thermolabile alpha-interferon-like substance, designated AL-IFN-alpha, has been found in non-processed normal human leukocyte IFN preparations as well as sera from patients with autoimmune or other chronic diseases. Little is known about origin, production and biological activity of these IFN activities. Monoclonal antibodies were obtained which proved highly selective in neutralizing AL-IFN-alpha in both anti-proliferative and antiviral tests. While the monoclonal antibodies were strict specific, polyclonal antibodies against various interferons showed less specificity in these tests. The results suggest that AL-IFN-alpha represents an antigenically distinct IFN-alpha subtype or, alternatively, a new lymphokine with antiproliferative and antiviral activity.

Using a high titred human leukocyte IFN alpha preparation which contained both acid- and thermolabile (AL-IFN alpha) and acid- and thermostable IFN alpha species in 9:1 proportion for immunization of BALB/c mice, five hybridomas secreting monoclonal antibodies that reacted with AL-IFN alpha were obtained. In antiviral and antiproliferative tests on HL-60 cells, their products showed high degree of specificity for AL-IFN alpha. The results suggest that both the "normal" leukocyte AL-IFN alpha and the IFN alpha found in sera of autoimmune and other chronic patients might belong to the same subtype of IFN alpha.

The effect of mild hyper- and hypothermic stress on release of selected hormones (somatotropin, noradrenaline, etc.), interferon (IFN), and activity of NK cells in the blood was examined in groups of young males during a 30 min exposure to 39 degrees C and 4 degrees C. A quick release of somatotropin was registered in 44% of examinees in the hyperthermic group, while the persons exposed to 4 degrees C reacted with a release of noradrenaline only. Concurrently, an elevation of NK cell activity was observed both in the subgroup releasing somatotropin after hyperthermic stress and in the group exposed to cold. Since these forms of mild stress did not lead to an appearance of IFN in the serum, the possibility of an NK cell activating effect of somatotropin and/or the adrenal hormones was tested. While the adrenal hormones stimulated the NK cell activity in vitro, no support for a similar role for somatotropin was found.

Several reports indicate that, in addition to disturbances found in the specific immune reactions, also the broader interferon /IFN/ system, including the NK-cells and IL-2 etc, shows misregulation in autoimmune disorders /Hooks et al., 1981, Waschke and Diezel, 1984, Rovenský et al., 1984, Lange et al., 1984 etc./.