Effects of naturally occurring glucosides, solasodine glucosides, ginsenosides and parishin derivatives on multidrug resistance of lymphoma cells and leukocyte functions.

Solamargine, solasonine, ginsenosides and parishin-related compounds were investigated for their effects on mdr efflux pump of lymphoma cells, and their effects on T cell proliferative assays and cell mediated immune functions, antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) cell activity of human peripheral mononuclear cells. Solamargine and solasonine were the only drugs which inhibited all of the tested immune functions; however, ginsenoside Rc and Rd enhanced T cell proliferative assays and marginally increased the NK cell activity. The majority of the compounds were not able to reverse the multidrug resistance of mouse lymphoma cells. However, ginsenosides Rc, Rd and parishin C were able to moderately reduce the activity of the efflux pump. Parishin, parishin C and crude extract significantly enhanced the ADCC reaction.

Effects of mycotoxins on human immune functions in vitro.

Immunosuppressive and carcinogenic Fusarium mycotoxins may appear in domestic food products. Therefore, the immunological effects of Fusarium mycotoxins were tested on human peripheral blood mononuclear cells from different blood donors. In the present study we investigated deoxynivalenol (DON), 3-acetyldeoxynivalenol, fusarenon-X, T-2 toxin, zearalenone, alpha-zearalenol, beta-zearalenol and nivalenol for their effects on T and B cells in a proliferation assay, antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) cell activity on human peripheral blood mononuclear cells. The concentrations applied in our experiments were similar to those which can be found in normal human peripheral blood system (0.2--1800 ng/ml). Among the eight mycotoxins tested, T-2 toxin, fusarenon X, nivalenol and deoxynivalenol exerted the highest immunosuppressing effect on human peripheral blood mononuclear cells in vitro. Mycotoxin-induced immunosupression was manifested as depressed T or B lymphocyte activity. Furthermore, by virtue of inhibition of NK cell activity, the protection against tumor development may also be attenuated.

Relationship between the occurrence of anti-SSA, anti-SSB autoantibodies and HLA class II alleles from the aspect of in vitro inhibitory effect of glucocorticosteroid on the antibody-dependent cellular cytotoxicity in patients with primary Sjögren's syndrome.

Though at present there is no evidence-based algorithm for the treatment of primary Sjögren's syndrome, it is generally accepted that glucocorticosteroid (GS) therapy must be introduced in cases with severe systemic manifestations. As the side-effects of the GSs are well known, it would be useful to know in advance how the patients will respond to this type of treatment. For this reason we measured the in vitro steroid sensitivity of 29 SS patients using inhibition of antibody dependent cellular cytotoxicity (ADCC) test by methylprednisolone compared to that of 28 controls. SS patients proved to be significantly less sensitive to GSs than controls (inhibition of ADCC reaction: 42.4 vs 53.1%; p < 0.01). This was especially true in SS patients with anti-SSA and/or SSB autoantibody positivity and with HLA-DR2 and/or -DR3 alleles. Comparing the results of the in vitro GS sensitivity and the clinical effectiveness of the previously applied corticosteroid therapy it seems that steroid inhibition of ADCC reaction has a predictive value in determination of in vivo sensitivity to GSs. However, in patients with decreased in vitro GS sensitivity a more expressed in vivo steroid sensitivity cannot be excluded.

Membrane associated antitumor effects of crocine-, ginsenoside- and cannabinoid derivates.

In the present work a systematic study was initiated with crocine, ginsenoside and cannabinoid derivatives on multidrug resistant mouse lymphoma cells, viral tumor antigen expression and some human leukocyte functions. Among saffron derivatives, crocin and picrocrocin, triglucosyl and diglucosyl crocetin were ineffective on the reversal of multidrug resistance of lymphoma cells. Ginsenoside increased drug accumulation and tumor antigen expression at 2.0-20.0 micrograms/mL. Some cannabinoid derivatives such as cannabinol, cannabispirol and cannabidiol increased drug accumulation, while cannabidiolic acid, delta-9-THC and tetrahydro-cannabidiolic acid reduced drug accumulation of the human mdr1-gene transfected mouse lymphoma cells. The reversal of multidrug resistance is the result of the inhibition of the efflux pump function in the tumor cells. Crocetin esters were less potent than crocin itself in the inhibition of EBV early antigen expression. However crocin and diglucosylcrocetin inhibited early tumor antigen expression of adenovirus infected cells, but triglucosylcrocetin was less effective at 0.01-1.0 microgram/mL. The crocin had no antiviral effect [on HSV-2 infected vero cells] up to 25 micrograms/mL concentration. Ginsenosides had a moderate inhibitory effect except ginsenoside Rb1 (was the less effective) on the drug efflux pump. Among the cannabinoid derivatives the cannabinol and cannabispirol increased drug accumulation, while cannabidiolic acid and delta-8-THC, delta-9-THC and tetrahydro-cannabinol reduced drug accumulation in multidrug resistant mouse lymphoma cells. It is interesting that ginsenosides had a chemical structure-dependent immunomodulating effect by enhancing the activity of NK-cells and ADCC activities.

Immunomodulating effect of 2,3,4,5-tetrahydro-1H-3-benzazepines (a new class of non-nucleoside inhibitors of reverse transcriptase).

The effects of newly synthesized, reverse transcriptase inhibitors, 3-benzazepines, for their effects on natural killer (NK) cell and blast transformation in human peripheral blood mononuclear cells were investigated. The most effective reverse transcriptase inhibitors were KF1, KF2 and KF3, which primarily suppressed immunological functions. Besides the inhibition of T cell proliferation, the benzazepines also show inhibitory effect on NK cell functions, in particularly, against large granular lymphocytes and monocytes. The B lymphocytes and Fc mediated killer functions were less inhibited.

Plasmid elimination and immunomodulation by 3-benzazepines in vitro.

For studying the mechanisms of biological activity on 3-benzazepines, antimicrobial effect, F'lac plasmid elimination activity (a plasmid curing effect on F'lac plasmid) and antibody-dependent cellular cytotoxicity (ADCC) test were performed. A weak antiplasmid effect was found at sub-inhibitory concentrations. A combination of [KF4] with verapamil [2] did not alter the ineffectivity, however, [KF4] could inhibit the antiplasmid effect of promethazine, as compared to the control (promethazine alone) plasmid curing effect. A competition between promethazine and [KF4] might exist in plasmid elimination effect. ADCC activity of human leukocytes was enhanced by KF1, KF2, KF3, DA and NE at 1.0 microgram/mL concentrations. The majority of 3-benzazepines [KS02, KM57, KN50, KE04, KI10, KP80] was ineffective for plasmid curing, however, inhibited the ADCC reaction, but they did not show a real dose-dependent effect.

Immunomodulating activities on cellular cytotoxicity and the blast transformation of human lymphocytes by 10-[n-(phthalimido)alkyl-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10 H-phenothiazin-10-yl)alkyl-1-ureas.

Phenothiazines, 10-[n-(phthalimido)alkyl-2-substituted-10H- phenothiazines, and 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1- ureas were investigated for their effects on antibody-dependent cellular cytotoxicity (ADCC), natural killer (NK) cells and the blast transformation of human peripheral blood mononuclear cells. All of the compounds dose-dependently suppressed mitogen-stimulated T cell proliferation. In contrast, a strong enhancing effect on NK cell activity was detected mostly in the case of 1-(2-choroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alk yl-1-ureas and their related compounds. The stimulating effect directly influenced the NK cells and was demonstrated at all tested concentrations.

Immunomodulating effect of acridine tautomers on eukaryotic cells.

The immunomodulating effect of some new amino- and imino-acridine derivatives, were investigated on antibody dependent cellular cytotoxicity (ADCC) and induced-blast transformation of lymphocytes. In different concentrations (2.0 x 10(-6) M, 4.0 x 10(-8) M and 2.0 x 10(-5) M) the drugs produced a suppression of PHA and ConA induced cell proliferative response except in the case of 2b, 2d and 2g amino-acridines. The suppressive effects were dose dependent and exhibited a higher inhibitory level in the case of imino-acridines. Some drugs at low concentration exerted a little enhancing effect on ADCC reaction.

Bone changes in young mice with impaired lymphoid system.

Disturbances of osseal growth were observed in young mice with their lymphoid system affected by antihymocyte serum or mitolactol (dibromodulcitol) treatment. These bone changes were similar to those observed in germ-free and neonatally thymectomized mice as well as in mice suffering from a graft vs. host reaction. Their severity was in direct correlation with the disturbance of the thymus dependent lymphoid system. Not only immunological adaptation but also normal bone growth appears to require an intact thymus and thymus dependent lymphoid system.