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PubMed1992

Glipizide-induced immunomodulation: inhibition of human mononuclear cell stimulation and macrophage-mediated islet cell killing in the BB rat.

Intensive insulin treatment, when combined with sulfonylurea drugs, may enhance remissions in new-onset type I diabetic patients. These clinical data suggest that sulfonylurea drugs may have immunosuppressive actions in addition to insulin secretory and sensitivity actions. Thus, studies were conducted in humans to determine if glipizide was immunomodulatory in vitro. Five, 10, and 15 micrograms/mL of phytohemagglutinin (PHA) and concanavalin A (Con A), and 0.5, 1.0, and 1.5 micrograms/mL of pokeweed mitogen (PWM) were incubated with normal human peripheral blood mononuclear cells. Maximum stimulatory indices were 52, 39, and 30 for PHA, Con A, and PWM, respectively. Additional incubations were performed in the presence of 1, 10(1), 10(2), 10(3), 10(4), and 10(5) ng/mL glipizide. Glipizide concentrations inhibiting mitogen stimulation approximately 50% (P less than .01 v nonglipizide control) were 1.0 ng/mL for PWM, 10 ng/mL for Con A, and 10(4) ng/mL for PHA. At higher glipizide levels, inhibition was 90% to 100%. To determine if glipizide immunomodulates diabetes-associated reactions, bio-breeding (BB) diabetic rat splenic macrophage-mediated islet killing was studied. Glipizide at 10(3) ng/mL inhibited islet killing by 60% (P less than .001). These preliminary data suggest that glipizide may have immunomodulatory actions not previously appreciated, and may be related to this drug's putative action in islet cell restoration.

Adult↗

PubMed1992

Lithium chloride and immunomodulation in taste aversion conditioning.

Lithium chloride has been used in many studies of conditioning to induce taste aversion behaviour, and in some experiments investigating conditioning effects on immunity it has been used on the assumption that it is immunologically neutral. The studies reported here, however, indicate that LiCl is not immunologically neutral and when used to endow a UCS with noxious properties to enhance the behavioural response in taste aversion conditioned immunosuppression, it may antagonize the residual immunosuppression following initial UCS administration and also the conditioned immunosuppression occurring after CS reexposure. Therefore, conclusions drawn from studies of behaviourally conditioned immunomodulation where LiCl is used as part of either the CS or UCS may require reevaluation.

Animals↗

PubMed1994

Cellular uptake and release of the immunomodulating fungal toxin gliotoxin.

Uptake of the immunomodulating agent gliotoxin into a panel of cells using biosynthetically radiolabelled 35S toxin showed rapid association of the toxin with all cell types studied with 70-85% of the total counts in the media becoming cell associated. A difference in kinetics was observed for cell lines when compared to the primary cells thymocytes, activated T-cells and macrophages. In the latter uptake was maximal after 10-15 min and radiolabel was lost from the cells as early as 100 min. In the cell lines studied, uptake was complete in less than 1 min with no loss of label after 100 min. The exception to this was a Wilms tumour line. Analysis of the fate of gliotoxin taken up into sensitive (activated T-cells) and resistant (human fibroblast) cells by HPLC showed: (a) up to 30% of the original gliotoxin taken up by sensitive cells was released as free gliotoxin over a 22 hr period. The remainder was metabolized to inorganic sulphate; (b) in T-cells gliotoxin is reduced to the dithiol form in significant amounts and this reduction may be modulated by glutathione; and (c) no reduced gliotoxin could be detected in the resistant fibroblast cell line 27Sk even though up to 50% of the original gliotoxin was still present in the free form in these cells at 22 hr. Gliotoxin became covalently associated with macromolecules in both cell types studied. Very little free gliotoxin is released into extracellular medium by the fibroblast cell line. Gliotoxin at 500 nM was found to induce apoptosis or programmed cell death in the Wilms tumour cell line but not in any other cell line studied, and this may account for the different kinetics of release of the toxin from the Wilms tumour cell line.

Animals↗

PubMed1993

Age related immunomodulation in murine splenocytes induced by delta-9-tetrahydrocannabinol (THC).

The purpose of this study was to investigate the immunomodulatory effects of THC (delta-9-tetrahydrocannabinol) on spleen cells of young (2 week), adult (2 month) and old (15 and 24 month) mice. THC has been shown by many investigators to suppress various immune parameters in adults. Since immune capabilities are already diminished at either age extreme, it seemed relevant to investigate the effect of this drug with aging. It was found that when spleen cells were stimulated with concanavalin A (Con A), phytohemagglutinin (PHA) or anti-CD3 antibody, the magnitude of the proliferation was greatest in the adult and less at either age extreme. When Con A or PHA stimulated cells were treated with varying doses of THC, the proliferation of cells was suppressed with the general pattern of suppression similar at all ages. However, the absolute magnitude of the resultant suppression was greater in young and old mice. In contrast, when the cells were stimulated with anti-CD3 antibody and THC, both the pattern of the immunomodulation as well as the absolute effects differed with age of the mice. In this regard, anti-CD3 stimulation and low doses of THC stimulated lymphocyte proliferation in the adult mice. This combination was found to increase CD3 positive cells of the Ly2 subclass (effector/suppressor) in the adult. At either age extreme, the THC induced enhancement of proliferation was not as apparent. In addition, the cells from mice at either age extreme were more readily suppressed at 7 micrograms THC than were adult cells. It appears, therefore, that age is an important variable in terms of considering the effects of drugs of abuse.

Adjuvants, Immunologic↗

PubMed1990

Diethyldithiocarbamate, a novel immunomodulator, prolongs survival in autoimmune MRL-lpr/lpr mice.

MRL-lpr/lpr mice die at an early age from a spontaneously developing systemic lupus erythematosus-like disease and are characterized by massive lymphadenopathy, hyperproliferation of Lyt-2/L3T4 (null) T cells, decreased responses to mitogens, thymic atrophy, and very high serum autoantibody levels. Diethyldithiocarbamate (DTC), an immunomodulator suggested to enhance T cells, was used to treat 12-week-old female MRL-lpr/lpr mice (25 mg/kg/week). DTC treatment significantly prolonged survival (50% mortality, 43 weeks vs 20 weeks). Increased survival was associated with decreased lymphadenopathy, decreased proliferation of null cells, restoration of impaired mitogen responses, decreased thymic atrophy, and decreased serum levels of anti-DNA and anti-histone antibodies. Studies of cell surface antigen phenotype demonstrated increased expression of Lyt-2 and macrophage surface antigens. No effect on L3T4 single staining cells was observed. These results show that DTC significantly alters the disease course in these mice and suggest that DTC may be a useful treatment for autoimmune disease.

Adjuvants, Immunologic↗

PubMed1993

Epitope mapping with peptides of Chi t I component III and immunomodulation of the Chi t immune response.

BACKGROUND: Hemoglobins of the Diptera family are known as aggressive inhalant allergens. METHODS: The whole sequence of the insect allergen Chi t I component III was studied for T-cell epitope activity in cell cultures of 15 sensitized patients with a panel of 17 overlapping synthetic peptides and 12 peptides obtained by tryptic cleavage. RESULTS: All but one of the peptides tested were found to be immunogenic. The nonstimulatory sequence 102-109 and two other tryptic peptides (69-90 and 110-135) were used in inhibition experiments. The Chi t I-induced proliferation was downregulated by all tested peptides when compared with stimulation with Chi t I alone. CONCLUSIONS: Because stimulation with phytohemagglutinin or tetanus toxoid was not influenced by the above-mentioned peptides, this mechanism seems to be specific for the antigen. Specific immunomodulation with nonstimulating peptides may offer new therapy approaches.

Adjuvants, Immunologic↗

PubMed1996

The novel immunomodulator, Linomide, stimulates interleukin-2-induced human natural killer (NK) cell and PHA-stimulated T cell proliferation from normal donors.

Donor-derived cell-mediated immunotherapy has been shown to be an effective tool for reinduction of remission in chronic myeloid leukaemia (CML) patients who have relapsed post-bone marrow transplantation (BMT). Linomide, quinoline-3-carboxamine (LS 2616), is a new immunomodulator shown to increase the number of NK precursors in mice in addition to upregulating the quantity of CD56(+), CD3(-) and CD16(+) NK cells in the peripheral blood of patients following autologous BMT (ABMT). We investigated the in vitro effects of Linomide on NK activity of normal human donors. Large granular lymphocytes (LGLs) and NK cells were incubated overnight with Linomide (0.02-4.8 mg/ml), recombinant human interleukin-2 (IL-2, 75 IU/ml), or a combination of both. Linomide, at 0.02-0.3 mg/ml, augmented IL-2-induced proliferation of LGLs and NK cells in an inversely proportional manner. In contrast, Linomide at 0.6-4.8 mg/ml inhibited IL-2-induced proliferation of LGLs and NK cells in a dose-dependent manner. Linomide was able to potentiate phytohemaglutinin-induced CD3(+) cell proliferation. In addition, supernatants derived from Linomide treated CD3(+) T cells were able to mimic the direct stimulatory effect of Linomide on activated NK cell proliferation. These supernatants were found to have low levels of tissue necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and therefore Linomide stimulation of NK and T cell proliferation may be due to its inhibitory effect on the secretion of these cytokines by activated CD3(+) T cells. Linomide had no effect on cytotoxicity nor on the phenotypic expression of resting and IL-2-activated LGLs or NK cells. In view of our results, Linomide could possibly play a potential role in adoptive cell-mediated immunotherapy post-BMT.

Adjuvants, Immunologic↗

PubMed1985

Chemistry of immunomodulators.

A large number of synthetic derivatives, inorganic compounds or naturally occurring substances are able to depress, regulate or enhance the immune response. Immunomodulators, among which some are chemically well defined and others are complex preparations, exhibit a great variety of chemical structures which are briefly reviewed, without details on their immunopharmacological properties. These molecules allow access to a new type of therapy which aims at acting on the host defense mechanisms.

Adjuvants, Immunologic↗

PubMed1986

Blood transfusions as an immunomodulator--a review.

Blood transfusions have been shown for two decades to prolong allograft survival. The mechanism is complex, involving both T lymphocytes and macrophages. In the last five years, transfusion induced immunosuppression has been shown to increase the rate of tumor growth and to increase susceptibility to infectious complications. Prevention of this immunosuppression may be possible by the concomitant use of immunomodulators which inhibit suppressor T lymphocyte function or block prostaglandin E production. A second potential but as yet unproven method is by use of frozen washed red blood cells when transfusions are required.

Adjuvants, Immunologic↗

PubMed1986

Influence of immunomodulators on T lymphocyte differentiation in ARC patients and resistance to LAV/HTLV III infection.

Isoprinosine and Imuthiol are non mitogenic immunomodulators active on T cell differentiation. In ARC patients, they modulate the circulating T cell receptor complex in terms of OKT4+ phenotype induction. This effect is not responsible for any expansion of the target population but for a partial inhibition of in vitro infection with LAV/HTLV III viral particles. At a clinical level, this means that these drugs may prove helpful in ARC patients when the virus has infected only a few helper cells.

AIDS-Related Complex↗

PubMed1988

Efficacy of an immunomodulating drug in immunodeficient and immunocompetent mice.

Bacillus subtilis culture filtrate (BSKR) was examined for its immunomodulating ability in the immunodeficient beige mouse and the immunocompetent Han:NMRI mouse strain. Following various application schemes the mice were challenged either subcutaneously with Escherichia coli or intranasally with Streptococcus pneumoniae. The mortality rates and the median of survival time were determined. Following subcutaneous application of BSKR Han:NMRI mice challenged with E. coli showed a decrease in mortality regardless of the application scheme. Using the beige mouse a protective effect was observed only after single applications of relatively low doses. Using Sc. pneumoniae as the challenge organism, a subcutaneous application of BSKR caused a decrease in mortality only if it was given on the day prior to infection. In both infection models the intranasal application of BSKR and/or of saline proved to be beneficial by either significantly decreasing the mortality or considerably increasing the survival time of beige and Han:NMRI mice.

Adjuvants, Immunologic↗

PubMed1988

The synthetic immunomodulator muramyl dipeptide (MDP) can stimulate activated B cells.

The synthetic immunomodulator muramyl dipeptide (MDP) has previously been shown to be able to synergize with lymphokines in enhancing the specific immune response of purified splenic B cells. Here, we have examined the effect of MDP in the process of B cell activation. We found that MDP alone was ineffective on the proliferation of either murine resting or in vivo activated B cells, whereas it enhanced the DNA synthesis of B cells once stimulated with anti-IgM antibodies. In agreement with these findings, cell cycle analysis by flow cytometry after acridine orange staining indicated that MDP by itself could not trigger the entry into the G1 phase of the cell cycle of nonactivated B lymphocytes. In contrast, in the presence of anti-IgM antibodies plus BSF-1, MDP promoted further cell cycle progression preferentially into the G1B compartment and also through the G2/M phase. A kinetic study showed that MDP was the most effective when added after the activation of B cells by anti-IgM antibodies plus BSF-1. Our present results suggest that functional receptors for MDP may be expressed on already cycling B cells.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1984

The effect of experimental conditions on the assessment of T cell immunomodulation by biological response modifiers (thymosin fraction five).

The coculture of spleen cells with specific antigens in the presence of thymosin fraction five (F5) results in the stimulation of the lymphocyte response. To observe the stimulation, a suboptimal responder-to-stimulator ratio must be utilized. Suboptimal assay conditions also are needed in immunization challenge studies in which thymosin F5 acts as an effective immunoadjuvant. The data reported here suggest that to study the efficiency of a biological response modifier, suboptimal assay conditions are best for observation of immunomodulation. We also report that thymosin F5, in addition to exhibiting adjuvantlike activity for T cells, is stimulatory in assays of mixed lymphocyte response and in the in vitro stimulation of cytotoxic T effector cells, following a mixed lymphocyte-tumor culture.

Adjuvants, Immunologic↗

PubMed1984

Induction of DNA polymerase alpha and terminal deoxynucleotidyl transferase in the human lymphoblastoid cell line Molt-4 by the immunomodulator bestatin.

The influence of the immunomodulator bestatin on the expression of terminal deoxynucleotidyl transferase and of DNA polymerase alpha and beta in Molt-4 cells has been studied. Bestatin was found to stimulate cell growth within the range of 0.3-33 microM, while concentrations higher than 300 microM were inhibitory during an incubation period of 48 h. The cell surface bound microsomal leucine aminopeptidase (bestatin receptor) activity decreased gradually during incubation at concentrations of bestatin above 3 microM. This effect was also observed after incubation with amastatin, but not with leupeptin or tunicamycin. Determinations of the activities of DNA synthesizing enzymes from bestatin-treated Molt-4 cells revealed a direct correlation between the decrease of the surface bound microsomal leucine aminopeptidase activity and the increase of the terminal deoxynucleotidyl transferase and DNA polymerase alpha activity; the DNA polymerase beta activity remained unchanged. From these experiments it is hypothesized that bestatin might cause a promoting effect on the differentiation processes of precursor T cells in vivo.

Adjuvants, Immunologic↗

PubMed1985

Staphage lysate: an immunomodulator of the primary immune response in mice.

The immunological enhancing activity of staphage lysate on the primary immune response of mice as reflected by specific heteroantibody production to a single antigenic stimulus and on immunoglobulin synthesis was determined. Staphage lysate was administered at different periods in relation to time of sheep erythrocyte injection so that both the inductive and the productive phase of the immune response could be evaluated. Treatment with staphage lysate induced pronounced enhancement of the hemagglutinin response by day 14 regardless of the dose or the time of its administration. Significantly higher antibody levels in the test groups were observed when compared with the control animals, peak antibody titers being 21 days following antigenic challenge. Furthermore, staphage lysate administered without an accompanying antigen evoked a heightened serum immunoglobulin level in mice for a period of more than 14 days after injection. IgG1, IgG2a and IgG2b were significantly elevated as a direct result of this treatment. This increased output of immunoglobulin synthesis and heightened hemagglutinin titers demonstrate that staphage lysate is not only an immunomodulator of cell-mediated immunity, as previously reported, but also an effective immunoadjuvant of the humoral antibody response capability in the host.

Adjuvants, Immunologic↗

PubMed1985

The restoration of impaired macrophage functions using as immunomodulator the Corynebacterium granulosum-derived P40 fraction.

Many microorganisms and compounds of microbial origin exhibit immunomodulatory activities and have been extensively used in immunotherapy of experimental animal tumors and in patients with neoplasia. In this paper we describe the effect of the C. granulosum-derived P40 fraction on the growth and metastatization of the transplantable epithelioma T8 of Guèrin. Moreover, we evaluated the effect of P40 treatment on several depressed macrophage functions of tumor-bearing rats. In particular, the phagocytic and chemotactic activities of such cells were studied, as well as the antiviral intrinsic and extrinsic activities against HSV-1 and the anti-Toxoplasma gondii activity. All these functions were depressed in untreated tumor-bearing rats. Administration of a single intravenous injection of P40 fraction led to the restoration of all depressed macrophage activities to normal values. In particular, the possibility of restoring the antimicrobial activity of macrophages from tumor-bearing rats by treatment with this immunomodulator is of great concern when one considers the increasing incidence of opportunistic infections in immunocompromised hosts. Results are discussed in terms of both the possible mechanism of action of P40 and of its possible target cells.

Adjuvants, Immunologic↗

PubMedDate not supplied

Activity of FCE 20696, a new synthetic immunomodulator, in models of viral and bacterial pathology.

The dibenzopyran derivative FCE 20696 is an immunomodulator which protects mice infected with several viral agents and with Mycobacterium tuberculosis. The compound is able to decrease the severity of the lung lesions caused by influenza virus infection. Doses ranging from 12.5 to 100 mg/kg are effective even after a single administration. Activity is demonstrated by intraperitoneal, subcutaneous and oral administration of the drug. In systemic infection with herpes simplex virus type 1, the 100 mg/kg dosage, administered subcutaneously, is able to increase both the percentage and the mean survival time of mice. To have effect by oral administration it is necessary to give the compound twice in the day. Moreover, some activity has also been observed in mice infected by M. tuberculosis, when the compound is administered orally at doses of 1-2.5 mg/kg twice weekly for 5 weeks, during the course of the disease.

Adjuvants, Immunologic↗

PubMedDate not supplied

Immunomodulation of proteoglycan-induced progressive polyarthritis by leflunomide.

Proteoglycan-induced arthritis is a mouse model displaying many similarities to human rheumatoid arthritis and ankylosing spondylitis which has been documented by clinical and histopathological studies. The development of the disease in genetically susceptible BALB/c mice is dependent upon the expression of both cell-mediated and humoral immunity to host mouse cartilage proteoglycan. Since both development and regression of acute inflammatory processes in joints correlate directly with the serum antibody level to mouse cartilage proteoglycan, it is believed that these autoreactive antibodies may play a key role in the pathological mechanism of proteoglycan-induced arthritis. The treatment of arthritic animals with an immunomodulating agent (leflunomide) suppressed acute inflammatory events, protected animals from new inflammatory episodes or acute exacerbations in chronically inflamed joints and blocked pathological processes in arthritic joints, which otherwise led to progressive deformities, ankylosis and the loss of articular cartilage. We conclude that the suppressive effect of leflunomide (HWA 486) in proteoglycan-induced arthritis primarily is due to the suppression of autoantibody formation and that the drug may be a potential agent in human therapy as well. Further, we feel that this novel model of murine polyarthritis will extend further the pharmacological repertoire necessary to discover innovative antirheumatic drugs.

Animals↗