Journal of immunopharmacology最新文献

Podophyllotoxin, a component of the plant resin Podophyllin, has been used as a clinical drug for many years. Recently it has been highly purified under the denomination of CPH-86. We here demonstrate that extremely low doses of the compound efficiently inhibit antibody responses to SRBC and prolong allogeneic skin graft survival in mice. In vitro immune reactions, such as mitogen and alloantigen induced proliferation and development of cytotoxic T cells, are also suppressed in a dose dependent manner. This effect does not seem to be due to direct cellular toxicity or to a shift in the kinetic pattern of the responses.

Isoniazid (INH) and hydralazine (HYD) are transglutaminase (TGase, E.C.2.3.2.13.) substrates containing catalytically recruitable hydrazyl groups. Since they can be expected to inhibit TGase-mediated cell functions by competing with physiological substrates, their effect upon allogeneically and lectin-induced proliferation of mononucleocytes and upon zymosan-induced chemiluminescence of phagocytes was studied. Both compounds inhibited chemiluminescence in a dose-dependent manner. ID50 of HYD was consistently below 20 microM, while that of INH was above 120 microM. Proliferation of immunocompetent cells was suppressed by HYD with an ID50 of 60 microM, INH was inhibitory only above 5000 microM. Analogs of both compounds not containing hydrazyl groups proved to be inactive. Control experiments indicated that inhibition is not due to toxicity or lipophilicity of the compounds, structural analogs lacking a hydrazyl moiety were inactive. It is suggested that, in vivo, HYD interferes with signal-induced TGase-dependent leucocyte functions essential for immunologic stability, and that the resultant dysregulation with disruption of self tolerance contributes to the HYD promoted lupus-like syndrome.

The in vivo administration of lymphokines is a new approach to immunotherapy with possible applications to the treatment of tumors and infectious processes. These lymphokines are produced in very small quantities and purification of these molecules has proven difficult. A rapid two step method was used to isolate different lymphokines from large quantities of conditioned media produced by the murine EL-4 cell line. Interleukin-2 (IL-2), colony stimulating factor (CSF) and macrophage activating factor (MAF) are lymphokines with distinct biologic activities and are secreted by the EL-4 cell line. Their isolation involved initial batch purification on trimethylsilyl-controlled pore glass beads followed by reversed phase high pressure liquid chromatography. Recovery of IL-2 activity was greater than 100% of initial activity. The specific activity of the purified IL-2 ranged from 2 X 10(6) to 3.6 X 10(7) U/mg protein. Colony stimulating factor (CSF) and macrophage activating factor (MAF) were also separated on the chromatographic columns. This technique is useful for the purification of large quantities of these lymphokines which have potential in vivo applications.

Miconazole was found to exert a biphasic influence on both cellular immune response and hepatic drug metabolism in adult Swiss mice. Indeed, at the dose of 2.5 or 12.5 mg/kg/twice daily via intraperitoneal route, miconazole depressed delayed-type hypersensitivity (DTH) to sheep red blood cells and hepatic drug metabolism as determined from barbiturate sleeping time, following one-day treatment. By contrast, at the same dose level, miconazole enhanced DTH and hepatic drug metabolism after a five-day administration schedule. Primary humoral response and colloidal carbon clearance were not affected. Although the underlying mechanism remains to be fully elucidated, these findings clearly suggest a close relation between modulation of the cellular immune response and activity of liver drug metabolizing enzymes.

The effect of Methotrexate (MTX) on pokeweed mitogen (PWM) induced immunoglobulin (Ig) production in vitro was studied over a range of 10(-4) - 10(-12)M MTX, using an enzyme-linked-immunosorbent assay (ELISA). MTX, at a concentration of 5 X 10(-9)M profoundly decreased all classes of Ig production, IgM greater than IgG greater than IgA. Plasma cell numbers, identified using polyclonal antihuman immunoglobulin, demonstrated a similar sensitivity to MTX. There was a paradoxical increase in IgM and IgG production at 5 X 10(-11)M MTX. Clinical implications of these findings are discussed.

A product isolated from Klebsiella pneumoniae and Escherichia coli, coded SLO4, has been shown to be effective in endogenous interferon induction in vivo in mouse when administered IP or IV, and in vitro with human leukocyte cultures. In these two systems induced interferon was defined. The inducer has not yet been characterized but seems not to belong to any components known to be interferon inducers such as viral particles, nucleic acids or endotoxins. An analytical study will be carried out to specify the constitution of this interferon inducer.

It is wellknown that theophylline yields phenotypic changes on suppressor cells. In the present study we investigated the possibility that theophylline could directly induce a suppressor activity on a lymphocyte subpopulation. We observed that a short preincubation (120 min at 37 degrees C) with theophylline (1mM) activates human peripheral blood lymphocytes to suppress mitogenic response of autologous cells. This activity was not evident on a T cell subpopulation depleted of theophylline-sensitive (T-sens) lymphocytes. Theophylline mediated suppressor activity is only present in the Concanavalin A stimulated cultures, thus suggesting a synergism between Concanavalin A and theophylline in the expression of non specific suppression. Moreover we observed that after a 24 hrs preincubation of lymphocytes in complete culture medium there was a complete loss of theophylline-induced suppression. Such a preincubation time also produced a decrease in the theophylline-mediated enhancement of intracellular 3', 5' cyclic adenosine monophosphate levels and the impairment of E-rosette formation, suggesting that theophylline acts mainly on a "short-lived" suppressor lymphocyte subset.

Previous studies have shown that delta-9-tetrahydrocannabinol (THC) suppresses T-lymphocyte proliferation when added to human cell cultures. We report that THC when added to mouse splenocyte cultures suppressed T-lymphocyte (Con A, PHA) and B-lymphocyte (LPS) mitogen-induced proliferation. Although the ED50 concentrations (5 micrograms/ml; 1.6 X 10(-5)M) of THC were similar for suppressing all three mitogen responses, higher threshold concentrations of drug were required to effect suppression of the T-lymphocyte mitogen responses. Complete suppression of T- and B-lymphocyte responses was achieved with THC concentrations (8 micrograms/ml or 2.6 X 10(-5)M) which were not directly toxic as judged by vital dye exclusion. The hydroxylated metabolite of THC, 11-hydroxy-THC, was observed to be much less potent in the inhibition of lymphocyte proliferation. However, as with the parent compound, B-lymphocyte responses appeared to be the most affected by the drug. Additional studies demonstrated that both T- and B-lymphocyte proliferation is rapidly suppressed following THC treatment, not affected by a 24 hr. pretreatment with THC, and not as readily suppressed by THC in cultures containing 20% serum. Thus, THC appears to inhibit both T- and B-lymphocyte proliferation with B-lymphocyte responses displaying greater inhibition at lower drug concentration. The 11-hydroxy metabolite is much less suppressive in this system than the parent compound.

Pharmacological doses of estrogens such as 17-beta estradiol (17- beta E) and diethylstilbestrol (DES) activate macrophages in a thymic-dependent manner in vivo. In this report, we investigated the direct in vitro effects of 17- beta E and its major metabolites on macrophage activation in response to lectin-stimulated lymphocyte supernatants containing macrophage-activating factor (MAF), a T cell lymphokine (LK). Activation was measured in terms of macrophage cytostasis against cultured tumor cells. As suggested by previous studies with quinone metabolites of benzene, the catechol estrogen metabolite 2-OH estrone (2-OH E) was the most potent metabolite at suppressing LK-induced macrophage activation. However, if macrophages were first LK-induced, and then exposed to estrogens before addition of tumor cells, then all the estrogens, including 2-OH E, enhanced cytostasis. These observations suggested membrane-mediated immunomodulation of macrophage function by estrogen metabolites and, indirectly, a role for the thymus in these effects via the maintenance of a mature, LK-producing T cell population necessary for macrophage activation.

A local graft versus host reaction between lymphocytes of Balb-c mice and its F-1-generation CB6F1 can be induced because of differences in products of the class II of the major histocompatibility complex (Ir). In this local mixed lymphocyte reaction mainly T-helper cells and B-cells are involved. An induction of a delayed type hypersensitivity reaction with oxazolon significantly decreases the local graft versus host reaction. Cyclosporin A depresses the local graft versus host reaction and the delayed type hypersensitivity in mice whereas Ciamexone, a 2-cyanaziridine derivative, very selectively only suppresses the local graft versus host reaction and increases the delayed type hypersensitivity.