The effect of three macrolide antibiotics, midecamycin acetate, josamycin, and clarithromycin, on human T-cell function was investigated in vitro. Midecamycin acetate and josamycin suppressed the proliferative response of peripheral blood mononuclear cells stimulated by polyclonal T-cell mitogens at concentrations between 1.6 and 8 micrograms/ml. At higher concentrations (40 to 200 micrograms/ml), all these drugs showed a marked inhibitory effect. At concentrations of 1.6 to 40 micrograms/ml, these drugs suppressed interleukin-2 (IL-2) production induced by mitogen-stimulated T cells, but not the expression of IL-2 receptor (CD25), in a dose-dependent manner. Therefore, the suppressive action on T-lymphocyte proliferation seems to be based on the ability of these drugs to inhibit IL-2 production by T cells. The drug also inhibited mixed lymphocyte reaction at the same concentrations. Combined treatment with these macrolides and the known immunosuppressants such as FK506 and cyclosporin A resulted in an increased inhibition of T-cell proliferation. The immunomodulatory properties of the antibiotics may have clinical relevance for modulation of the immune response in transplant patients and in patients with inflammatory diseases.
Elevated serum ferritin levels have been reported in a number of pathological states. These observations indicate that cells of the immune system can participate in the prevention of potential tissue toxicity from iron accumulation, and iron and iron-binding protein have important effects on immune systems. Ferritin is generally regarded as an intracellular iron storage protein. However, small amounts of ferritin circulate in the serum of normal individuals, and the physiological role of serum ferritin remains obscure. Although the function of ferritin is inevitably linked to iron metabolism, a role for ferritin in hematopoiesis and the immune system has drawn attention for years. Ferritin has an inhibitory effect on the in vitro growth of human hematopoietic progenitor cells and on the proliferation of T lymphocytes in vitro. Recently we report that ferritin may directly suppress the differentiation of human B lymphocytes maturing into antibody producing cells in vitro. In the present review, we summarise this field of research.
A 23-yr-old male patient with normotensive primary aldosteronism is reported. He complained of muscle weakness, polydipsia, and polyuria. His blood pressure was generally 118/60 to 124/70 mm Hg. Serum sodium, potassium and chloride were 152.2.2, and 108 meq/liter, respectively. Arterial blood pH, glomerular filtration rate, renal plasma flow and circulating plasma and blood volumes were normal, and plasma bicarbonate was normal or elevated. PRA was 0.16 ng/ml.h and did not increase significantly after sodium deprivation, ambulation, and iv furosemide injection. Plasma aldosterone was 64.1 ng/100 ml. He showed pressor responses to infused angiotensin II and norepinephrine which were similar to those in normal men. Adrenal scintiscanning after iv injection of [131I]6 beta-iodomethyl-19-nor-cholesterol during dexamethasone administration showed dense uptake on the right adrenal and minimal uptake on the left. Intravenous infusion of angiotensin III at a rate of 20 ng/kg. min for 30 min did not cause an increase in plasma aldosterone. Serum electrolytes became normal after spironolactone but not after dexamethasone. At surgery, the right adrenal, bearing a benign adenoma, was removed. After surgery, blood pressure was unchanged, but all biochemical abnormalities disappeared. The cause of this normotension remains to be elucidated, but the diagnosis criteria of primary aldosteronism should now be partly modified.
SUMMARYBnimncriptine (BRC). a dopamine lypc 2 agonist, prevents secretion of pituitary prolactin (PRL). BRC has been slioun to itnpair lymphocyte responsiveness toward antigenic stitiuilation by decreasing serum PRL levels, Hvpoprolactinaemia induced by BRC produces a similar immunosuppressive cflect. as observed in hypophysectomized rats, which is restored by the administration of PRL, Therefore, the immunosuppression induced by BRC has been inlerpreted as the result of liypoprolactinaemia. However, ihc direct mechanism of BRC in imtiuinc response has never been evoked. We recently reported that BRC has an immunosuppressive activity on human B lymphocyte function in vitro. In the present study we demonstrate that BRC suppresses T cell proliferation by means of blocking IL-2 production by T cells as well as mixed lymphocyte reaction (MLR) in a dosedependent manner. We could noi detect the immimorcaciivc PRLacliviiy in ihc conditioned medium from polyclonai T cell tnilogen-stimulatcd T cell cultures. Then, the immunosuppressive acliviiy of BRC on human T cell function appeared lo be independent of its hypoprolaclinaemic effect. Treatment with low-dose cyclosporin A(CsA) or FK5()6 in combination with BRC has proved more crtcctive than cilhcr drug alone in suppression of T cell proliferation and CD25 aniigen expression. Thus, the therapeutic applicalion of BRC in combinalion with immunosupprcssanls may enhance the immunosuppressive effect, while at the same time decreasing the toxicity.
Recent investigations have shown that some antibiotics also work as immunomodulators. We have recently reported that fosfomycin (FOM) has an immunomodulatory effect on human B-cell activation. FOM is a unique antibiotic which is chemically unrelated to any other known antibacterial agent. In the present study, we examined the effect of FOM on human T-cell function. FOM inhibited the proliferation of human lymphocytes induced by polyclonal T-cell mitogens in a dose-dependent manner. FOM also strongly suppressed mixed lymphocyte reaction and interleukin-2 (IL-2) production by T cells. Moreover, FOM inhibited the expressions of IL-2 receptor (CD25) and transferrin receptor (CD71) on the activated T-cell surfaces. These data suggest that FOM may block the T-cell division during the transition from G1 to S phase of the cell cycle. sheep erythrocytes (E). T cells were obtained by treating E+ cells with lysing buffer (NH4Cl:KHCO3).Reagents. Fosfomycin sodium (1R, 2S-1,2-epoxypropyl phosphonic acid; FOM) and enantiomer of fosfomycin (1S, 2R-1,2-epoxypropyl phosphonic acid) were supplied by Meiji Seika Ltd., Tokyo, Japan. FK506 and Cs-A were donated by Fujisawa Pharmaceutical Co. Ltd. (Osaka, Japan) and Sandoz (Basel, Switzerland), respectively. These drugs were dissolved in ethanol, further diluted in medium, and added to the cultures. Phytohemagglutinin (PHA) and pokeweed mitogen (PWM) were obtained from Difco Laboratories (Detroit, Mich.) and GIBCO Laboratories (Grand Island, N.Y.), respectively. Recombinant human interleukin-2 (IL-2) was donated by Shionogi Pharmaceutical Co. (Osaka, Japan). Fluorescein isothiocyanate-conjugated anti-CD25 monoclonal antibody (IL-2R1) and fluorescein isothiocyanate-conjugated anti-CD71 monoclonal antibody (T9) were purchased from Coulter Immunology (Hialeah, Fla.).Measurement of lymphocyte proliferation. Lymphocytes were cultured in triplicate in 96-well flat-bottomed microplates at 37°C, 5% CO2. The culture medium consisted of RPMI 1640 supplemented with 10% heat-inactivated fetal calf serum, streptomycin (100 ,ug/ml), penicillin (100 U/ml), and 2-mercaptoethanol (0.005 mM
The biological activity of des-Asp1-angiotensin I (des-Asp1-AI) was studied in five normal men. An iv infusion of 300 ng (258 pmol)/kg.min des-Asp1-AI caused a remarkable rise in blood pressure, a decrease in PRA, and an increase in plasma aldosterone concentration. The pressor and steroidogenic actions of this dose of des-Asp1-AI were slightly less than those of 100 ng (111 pmol)/kg.min des-Asp1-angiotensin II [Angotensin III (AIII)] which we reported previously and were abolished by a single oral administration of 100 mg of a converting enzyme inhibitor, SQ 14225. These results indicate that in man, as in animals, a rise in blood pressure and an increase in plasma aldosterone concentration after an infusion of des-Asp1-AI are entirely due to the actions of AIII converted from this nonapeptide, and that the conversion rate of des-Asp1-AI to AIII in normal men is less than 43%. This is much less than the conversion rate of angiotensin I to angiotensin II. It seems unlikely that des-Asp1-AI has physiological significance in the human renin-angiotensin-aldosterone system.
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