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PubMed2002

Immunomodulating effects of tofizopam (Grandaxin) and diazepam in vitro.

Benzodiazepines (BDZs) are known to act not only in the central nervous system, but on peripheral cells and tissues binding to the peripheral-type benzodiazepine receptors. In the present study, the influence of two different BDZs (diazepam (Dz) and tofizopam (Tof) on several immune functions has been examined in vitro. Some differences between Dz and Tof in their effects on human lymphocyte proliferative response, changes in glucocorticoid-induced suppression of cell proliferation and influence on cytokine production (tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2)) have been determined. Dz suppressed mitogen-induced peripheral blood mononuclear cell (PBMC) proliferation, enhanced dexamethasone-induced inhibition of PBMC proliferative response, and suppressed lymphocyte production of TNF-alpha and IL-2. Tof usually enhanced PBMC proliferation and IL-2 production in low and moderate doses, but in high doses it suppressed both. Tof in all investigated doses enhanced dexamethasone-induced suppression of lymphocyte proliferation and depressed TNF-alpha production. Thus, both Dz and Tof are shown to have immunomodulating effects in vitro. Tof, opposite to Dz even in the therapeutic doses, is able to enhance in vitro mitogen-induced lymphocyte proliferation and IL-2 production.

Anti-Anxiety Agents↗

PubMed1998

Immunomodulating activities of a natural alpha1-acid glycoprotein and its carbohydrate chains attached to the protein-free polymer.

Immunomodulating effects of a neoglycoconjugate created on the basis of alpha1-acid glycoprotein (AGP) carbohydrate chains and synthetic protein-free carrier have been investigated. It was demonstrated that this pseudo-AGP suppressed PHA- or anti-CD3 antibody-induced lymphocyte proliferation in a dose-dependent manner. Pseudo-AGP revealed a similar antiproliferative effect as the natural AGP samples. Stimulation of the LPS-induced proinflammatory cytokine production by mononuclear cells treated with both natural and pseudo-AGP has been also demonstrated. These data show that carbohydrate chains of AGP play a crucial role in the studied biological effect realization.

Carbohydrates↗

PubMed2005

Transfusion immunomodulation or TRIM: what does it mean clinically?

Evidence from a variety of sources indicate that allogeneic blood transfusions can induce clinically significant immunosuppression, as well as other effects, in recipients. This clinical syndrome is generally referred to in the Transfusion Medicine literature as transfusion-associated immunomodulation, or TRIM. TRIM has been linked to an improved clinical outcome in the setting of renal allograft transplantation. Possible deleterious TRIM-associated effects include an increased rate of cancer recurrence and of post-operative bacterial infection. The recognition that TRIM can increase morbidity and mortality in allogeneically transfused individuals has become a major concern for those involved in Transfusion Medicine. However, based on available randomized controlled trials, whether TRIM predisposes recipients to increased risk for cancer recurrence and/or bacterial infection is still unproven. In contrast, data from experimental animal studies suggest that TRIM is an immunologically mediated biological effect, associated with the transfusion of allogeneic leukocytes; an effect, which can be completely ameliorated by the pre-storage leukoreduction of blood products. Relevantly, several (n = 5) recent large observational trials have provided important evidence for the existence of deleterious TRIM and related effects (mortality and organ dysfunction) of leukocyte-containing allogeneic cellular blood products. These latter data suggest that allogeneic blood product transfusions, containing leukocytes, are associated with an increased risk both for mortality, and organ dysfunction in recipients.

Animals↗

PubMed1999

Preparation of novel conjugates involving immunomodulating peptidoglycan monomer.

Peptidoglycan monomer, the disaccharide pentapeptide beta-D-Glcp-N-Ac-(1-->4)-D-Murp-N-Ac-L-Ala-D-mesoA2pm- (epsilonN H2)-D-Ala-D-Ala (PGM) is an immunomodulator. PGM and/or its derivative N-tert-butyloxycarbonyl-L-tyrosyl peptidoglycan monomer (Boc-Tyr-PGM) were coupled to two polysaccharides: the glucuronoxylomannan (GXM) from Cryptococcus neoformans, type B, solubilized by ultrasonic irradiation (MW 12-400 kDa) and to the dextran FP 70 (MW 70 kDa). Both polysaccharides were activated by CNBr. Initially, unprotected PGM was coupled via its amino group to GXM. The reactions yielded 42%-52% of the conjugate, containing only 0.18%-0.31% of PGM. In another approach Boc-Tyr-PGM (having its amino group blocked) was reacted via its free carboxyl group. Both CNBr-activated polysaccharides were first coupled to adipic acid dihydrazide (ADH) and then subsequently coupled to Boc-Tyr-PGM. The dextran conjugate (approximately 80% yield ) contained 6.3% of Boc-Tyr-PGM. The isolation of GXM conjugate required several modifications and it was obtained in lower yield (approximately 30%) but contained 13.7% of Boc-Tyr-PGM. Both conjugates were water soluble and apyrogenic and suitable for further testing of biological activity.

Adjuvants, Immunologic↗

PubMed2005

Methamphetamine administration produces immunomodulation in mice.

The abuse of methamphetamine (MA) is an increasingly growing problem globally and produces serious side effects. In the present study, the immunomodulating effects of MA were examined on the immune system after MA (5 mg/kg body weight) was administered daily orally for 14 d. The immune system was evaluated by the antibody response to sheep red blood cells (SRBC; plaque assay and serum immunoglobulin [Ig] G), natural killer (NK) activity, lymphocyte subpopulations in the spleen and thymus, and concanavalin A (Con A)- and lipopolysaccharide (LPS)-stimulated lymphocyte proliferation using splenocytes. Body weight, spleen weight, and thymus weight generally decreased in MA-treated mice. MA treatment induced an increase in the percentage of CD4(+) cells with simultaneous decrease in the percentages of CD8(+) and double-positive CD4(+)CD8(+) in thymus. MA inhibited the IgM plaque-forming cell number, and lowered the level of IgG, the proliferation of mitogen-stimulated B and T cells, and the growth of granulocyte-macrophage colony-forming units (CFU-GM). Exposure to MA also decreased interleukin-2 production by splenocytes. In contrast, splenic NK activity in exposed mice was significantly enhanced. Taken together, data indicate that the immune system was suppressed by oral MA exposure.

Animals↗

PubMed2005

Comparison of immunomodulator mRNA and protein expression in the lungs of Stachybotrys chartarum spore-exposed mice.

Stachybotrys chartarum is an important toxigenic fungus that has been associated with respiratory disease onset in animals and humans. It can be separated into macrocyclic trichothecene-producing and nonproducing chemotypes based on secondary metabolite production. However, effects of spores of the two chemotypes on lung inflammatory responses are poorly understood. In this study, real-time reverse-transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA) were used to investigate time-course (1, 3, 6, 24, and 48 h post-instillation [PI]) relationships in mice intratracheally exposed to 300 spores/g body weight of a macrocyclic trichothecene-producing (JS 58-17) and a nonproducing (JS 58-06) S. chartarum isolate and of Cladosporium cladosporioides. There were marked differences in the magnitude and temporal patterns of mouse lung immune responses to intratracheal exposure to spores of these species at this spore dose. Both macrophage inflammatory protein 2 (MIP-2) and surfactant protein-D (SP-D) mRNA expression were significantly upregulated in lungs of JS 58-17-treated animals compared to that of all other treatment animals at 6 and 24 h PI. Heightened mRNA expression of these immunomodulators combined with comparatively depressed MIP-2 and tumor necrosis factor (TNF)-a protein expression suggests that the action of macrocyclic trichothecenes sequestered in 58-17 spores is involved. Interestingly, TNF-a protein expression in all spore treatment animal groups was also significantly increased over that in saline controls. Similarities in expression among all spore treatment animals suggest that chemicals other than toxic secondary metabolites, and possibly spore-sequestered 1,3-beta-D-glucan, may contribute to lung pathogenesis.

Animals↗

PubMed1983

Evaluation of ELISA for detecting in vivo chemical immunomodulation.

Immunotoxicology is a relatively new field of investigation and is becoming recognized and used by toxicologists involved in drug and chemical testing. The purpose of this study was to evaluate the enzyme-linked immunosorbent assay (ELISA) as a means of quantitating humoral immune responses in rats exposed to immunomodulating chemicals. The ELISA proved to be highly sensitive and quantitative, simple to perform, and reliable. The assay is also economically feasible and automated so that large numbers of samples can be analyzed at one time. The antigen used in the study was bovine serum albumin, and the immunosuppressive chemicals used to validate the system were lead, polychlorinated biphenyl, cyclophosphamide, and dexamethasone. Practical application of the procedure to immunotoxicology testing is discussed.

Animals↗

PubMed1989

Immunomodulation in C57Bl/6 mice following consumption of halogenated aromatic hydrocarbon-contaminated coho salmon (Oncorhynchus kisutch) from Lake Ontario.

This report describes studies designed to assess the immunomodulatory effects associated with the consumption of coho salmon containing halogenated aromatic hydrocarbons (HAHs) and other compounds naturally bioaccumulated from Lake Ontario. Diets containing 33% coho salmon from Lake Ontario or the Pacific Ocean were fed to juvenile C57Bl/6 mice for 2-4 mo. Following 60 d, the mice that consumed Lake Ontario salmon had reduced IgM, IgG, and IgA plaque-forming cell responses to sheep erythrocytes. No changes were observed in total numbers of spleen lymphocytes, total T-lymphocytes or T-lymphocyte subsets as determined by flow cytometry. Cellular immunity, assessed by the cytotoxic T-lymphocyte response to allogeneic tumor target cells, was not altered following dietary exposure to Lake Ontario coho salmon for 4 mo. The observed humoral immunomodulation correlated with elevated PCB levels in the Lake Ontario salmon diets. The levels of pollutants such as mercury, tin compounds and other metals, PCDDs, and PCDFs were not examined.

Animals↗

PubMed2002

Immunomodulation by biphalin, dimeric synthetic opioid peptide, and its analog.

The opioid pentapeptides called enkephalins were originally described as the endogenous ligands for the opioid receptors. Although their precise physiological significance still remains elusive, the enkephalins have been reported to exhibit analgesic, antidepressant, antianxiety and anticonvulsant activities. In addition, enkephalins have also been shown to act as immunomodulator. The first generation of dimeric peptides was derived from enkephalins. Biphalin [(Tyr-D-Ala-Gly-Phe-NH)2] is a bivalent opioid analog containing two tyrosine residues. We have evaluated the immunomodulatory properties of biphalin and its analogs in various in vitro tests. We report that biphalin and one of its analogs [Tyr-D-Ala-Gly-Phe-NH.NH-Phe(p-Cl)-H] stimulate human T cell proliferation, natural killer (NK) cell cytotoxicity in vitro and interleukin-2 (IL-2) production. Biphalin and its analog also released chemokine like factor in the culture supernatant that was responsible for increased chemotaxis of monocytes. Furthermore, these peptides inhibited tumor necrosis factor (TNF-alpha) production in lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) and nitric oxide (NO) production in mouse macrophage cells, RAW 264.7. Our observations suggest immunomodulatory property of biphalin and its analog.

Adjuvants, Immunologic↗

PubMed2004

Immunomodulating effects of CKBM on the cytokine production in peripheral blood mononuclear cells (PBMCs) from healthy volunteers.

The current study investigated the immunomodulating effect of CKBM on cytokine induction in peripheral blood mononuclear cells (PBMCs) isolated from 20 healthy volunteers. Cytometric Bead Analysis (CBA) was used to study IL-2, IL-4, IL-6, IL-10, TNF-alpha and IFN-gamma. TNF-alpha and IL-6 were significantly increased in a CKBM dose- and time-dependent manner. Flow cytometry analysis showed an increased intracellular staining of IL-6 but not of TNF-alpha in CKBM treated PBMCs. In addition, MTT cell cytotoxicity assay showed that CKBM concentrations below 5% did not significantly affect the metabolic activities of PBMCs. The current study indicated that CKBM may modulate the immune response by inducing the secretions of TNF-alpha and IL-6, which are cytokine mediators of innate immunity and inflammation preparing or "priming" the body to combat diseases.

Adult↗

PubMed1991

Heterogenous graft rejection pathways in class I major histocompatibility complex-disparate combinations and their differential susceptibility to immunomodulation induced by intravenous presensitization with relevant alloantigens.

The present study investigates the heterogeneity of graft rejection pathways in class I major histocompatibility complex (MHC)-disparate combinations and the susceptibility of each pathway to immunomodulation induced by intravenous presensitization with alloantigens. Depletion of CD8+ T cells was induced by repeated administration of anti-CD8 monoclonal antibody. CD8+ T cell-depleted mice failed to generate anti-allo class I MHC cytotoxic T cell (CTL) responses but exhibited anti-allo class I MHC T cell responses, such as mixed lymphocyte reaction (MLR)/IL-2 production, that were induced by CD4+ T cells. In contrast, donor-specific intravenous presensitization (DSP), as a model of donor-specific transfusion, induced almost complete elimination of CD4+ and CD8+ T cell-mediated MLR/IL-2 production, whereas this regimen did not affect the generation of CTL responses induced by DSP-resistant elements (CD8+ CTL precursors and CD4+ CTL helpers). Prolongation of skin graft survival was not induced by either of the above two regimens alone, but by the combination of these. Prolonged graft survival was obtained irrespective of whether the administration of anti-CD8 antibody capable of eliminating CTL was started before or after DSP. The combination of DSP with injection of anti-CD4 antibody also effectively prolonged graft survival. However, this was the case only when the injection of antibody was started before DSP, because such antibody administration was capable of inhibiting the generation of CTL responses by eliminating DSP-resistant CD4+ CTL helpers. These results indicate that (a) the graft rejection in class I-disparate combinations is induced by CD8+ CTL-involved and -independent pathways that are resistant and susceptible to DSP, respectively; (b) DSP contributes to, but is not sufficient for, the prolongation of graft survival; and (c) the suppression of graft rejection requires an additional treatment for reducing DSP-resistant CTL responses. The results are discussed in the context of potential clinical application in attempts to inhibit the generation of DSP-resistant CTL responses upon the prospective DSP.

Animals↗

PubMed1998

Protection against experimental intraabdominal sepsis by two polysaccharide immunomodulators.

Two immunomodulating polysaccharides, poly-(1-6)-beta-glucotriosyl-(1-3)-beta-glucopyranose (PGG)-glucan and Bacteroides fragilis polysaccharide A (PS A), were evaluated for the prevention of mortality and abscess formation associated with experimental intraabdominal sepsis. Prophylactic treatment with a combination of these compounds significantly reduced mortality (8% vs. 44% in the saline-treated control group) and the incidence of abscesses (30% vs. 100% in the saline-treated control group) after challenge with rat cecal contents. These compounds were also effective when administered therapeutically after bacterial contamination of the peritoneal cavity. PS A treatment conferred long-term protection against abscess formation and resulted in significantly fewer total aerobes and anaerobes in the peritoneal fluid of animals challenged with cecal contents. These data demonstrate the usefulness of two immunomodulatory polysaccharides in preventing experimental intraabdominal sepsis in the absence of antimicrobial therapy and may represent a new adjunct to antibiotic regimens currently used to prevent clinical cases of this disease.

Abdominal Abscess↗

PubMed2001

Effects of the immunomodulator linomide on macrophage migration and myelin phagocytic activity in peripheral nerve trauma: an experimental study.

Wallerian degeneration after peripheral nerve transection leads to the phagocytosis of degenerated myelin and axon components by macrophages. These phagocytes are recruited from the systemic circulation and Wallerian degeneration may therefore be used as a model for myelin removal by hematogenous macrophages, a feature that is also a hallmark of demyelinating diseases of the central and peripheral nervous system. The immunomodulator linomide has been shown to be effective in the treatment of experimental demyelinating diseases although the exact mode of its action is not yet defined. The present study investigated the effect of linomide on monocyte invasion and myelin phagocytosis after sciatic nerve transection. Linomide had a dual effect in Wallerian degeneration. Monocyte migration from the circulation to the damaged nervous system was significantly reduced. Additionally, the myelin phagocytic capacity of macrophages was impaired, finally resulting in a significant delay in the removal of myelin. The present experiments may provide an explanation for the effects of linomide during the course of demyelinating diseases of the nervous system.

Adjuvants, Immunologic↗

PubMed2000

Immunomodulation and adenoviral gene transfer to the lungs of nonhuman primates.

Previous data from our laboratory and others have demonstrated a critical role for the CD4+ T lymphocyte in in vivo immune responses to recombinant adenoviral vectors. In rodent models, this subset of T cells is required for T cell proliferation, subsequent cytotoxic T cell generation, and production of anti-adenoviral antibodies by B cells. Both depleting and nondepleting anti-CD4 antibodies can attenuate these immune responses to recombinant adenovirus. On the basis of these data, we hypothesized that a nondepleting CDR-engrafted anti-human CD4 antibody (OKT4A) with cross-reactivity to rhesus macaques would attenuate both T and B cell responses to intrapulmonary administration of recombinant adenovirus and permit prolonged reporter gene expression and permit secondary gene transfer. Juvenile rhesus macaques were treated with PBS or OKT4A antibody (10 mg/kg) daily beginning 1 day prior to and up to 11 days after gene transfer. OKT4A resulted in significant attenuation of lymphocyte recruitment into the lung, lymphocyte-proliferative responses to both adenovirus capsid proteins and transgene protein, and adenovirus-induced interferon-gamma elaboration in whole blood and hilar lymph nodes. However, OKT4A was ineffective in attenuating adenovirus-induced IL-4 production in whole blood or hilar lymph nodes, generating neutralizing anti-adenoviral antibodies, or permitting secondary gene transfer. As all the monkeys in this protocol had baseline-detectable anti-adenoviral antibodies by ELISA that were nonneutralizing, analogous to most patients with cystic fibrosis, we postulate that anti-CD4 did not block the proliferation of memory B cells. Moreover, these data suggest that for transient immunomodulation to be successful, strategies need to focus specifically on B cell activation independent of CD4+ T cell help.

Adenoviridae↗

PubMed2001

Clinical tolerance and profile of cytokine induction in healthy volunteers following the simultaneous administration of ifn-alpha and the synthetic immunomodulator murabutide.

As the therapeutic use of interferon-alpha (IFN-alpha) is limited by a dose-dependent toxicity and variable efficacy, ways of improving the therapeutic index of the cytokine are being sought. Murabutide (N-acetyl muramyl-L-alanyl-D-glutamine-O-n-butyl-ester) (ISTAC Biotechnology, Lille, France) is a safe synthetic and clinically acceptable immunomodulator that enhances the biologic activities of IFN-alpha in different experimental models. We evaluated in healthy human volunteers tolerance of the coadministration of Murabutide with increasing doses of IFN-alpha. The simultaneous administration of the two drugs was well tolerated without any increased or prohibiting toxicity, and all recipients experienced side effects that were similar to those observed after the administration of IFN-alpha alone. We also profiled the serum levels of cytokines induced following coinjection of the two drugs. We mostly detected an induction of anti-inflammatory cytokines and of human immunodeficiency virus type 1 (HIV-1)-suppressive beta-chemokines, in the absence of release of key proinflammatory cytokines. Therefore, the simultaneous administration of Murabutide and IFN-alpha is well tolerated and does not lead to increased toxicity. In addition, the selectivity in the profile of cytokines and chemokines induced following the coadministration of Murabutide and IFN-alpha points to the potential use of this combination in the treatment of inflammatory diseases and chronic viral infections.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1997

Direct tumor growth suppressive effect of melanoidin extracted from immunomodulator-PSK.

Melanoidin, which belongs to the melanin group of molecules, was extracted from the polysaccharide biological response modifier PSK. Melanoidin was cultured together with HCT-15 cells derived from human colon cancer and with AGS cells derived from human gastric carcinoma. After four days of culture, cell count was compared with that of the control cells. Significant suppression was observed, that is, 50% suppression was shown at concentrations of melanoidin between 200 and 100 micrograms/ml. A histogram generated by flow cytometry showed elevation of the tetraploid peak and of that between diploid and tetraploid peaks, suggesting blockage of S phase and G2 to M phase of the cell cycle. Thus, melanoidins contained in the immunomodulator PSK revealed to have a direct tumor cell growth inhibitory effect.

Adjuvants, Immunologic↗

PubMed1989

Recombinant bovine interferon-gamma as an immunomodulator in dexamethasone-treated and nontreated cattle.

Three dosages (0.1, 0.5, and 2.5 mg/animal, subcutaneously), of recombinant bovine interferon-gamma (rBoIFN-gamma) were evaluated for their in vivo influence on neutrophil function and lymphocyte blastogenesis in cattle. The optimal of the three dosages tested (0.5 mg/animal or 1.1 x 10(6) U/animal) was then evaluated for its influence on neutrophils and lymphocytes in both normal and dexamethasone-treated cattle. One animal, which received 2.5 mg of rBoIFN-gamma, died by 24 h after administration due to acute diffuse interstitial pneumonia with interlobular edema and emphysema. The two highest dosages used caused fever at 24 h and the highest dosage caused a decrease in lymphocyte blastogenesis at 24 h after administration. The influence of rBoIFN-gamma on neutrophil function was dose dependent and depended on the baseline values for neutrophil function. Random migration by neutrophils was consistently inhibited in animals that received 0.5 mg or more of rBoIFN-gamma. Staphylococcus aureus ingestion and antibody-dependent cell-mediated cytotoxicity by neutrophils was enhanced by rBoIFN-gamma treatment in both dexamethasone-treated cattle and in nondexamethasone-treated cattle, which had relatively low values for these parameters before treatment. Iodination by neutrophils was also enhanced by rBoIFN-gamma when either a suboptimal concentration of neutrophil stimulant was used or when the cattle were treated with dexamethasone. In summary, the rBoIFN-gamma had greater immunomodulator activity in immunosuppressed than in normal cattle. The in vivo influence of rBoIFN-gamma therefore depends on the physiologic status of the animal.

Adjuvants, Immunologic↗

PubMed1990

Immunomodulation by recombinant rat interferon-gamma in vivo.

Most studies on the immunomodulating effects of interferon-gamma (IFN-gamma) have been performed in vitro, using recombinant mouse and human IFN-gamma preparations. Recently, recombinant rat IFN-gamma (rRIFN-gamma) became available, enabling extensive studies with this new preparation in vivo. In the present study a LEW rat model was used to determine the efficacy of rRIFN-gamma on immune functions in vivo. LEW rats were treated with rRIFN-gamma by continuous intravenous infusion at a dosage of 1.5 x 10(5) U/kg.h for 2 consecutive days. Twelve hours after cessation of rRIFN-gamma administration immune functions, including NK-cell activity, phagocytosis, and mitogen-induced blastogenesis, were assessed. All experimental animals displayed a marked reduction in the number of peripheral blood and bone marrow cells when compared with controls (p less than 0.005). Assessment of immune functions revealed a significant enhancement of NK-cell activity (p less than 0.001), phagocytosis (p less than 0.05), and mitogen-induced blastogenesis (p less than 0.05). These findings indicate that rRIFN-gamma, when given in high dosages, has a stimulatory effect on various immune functions, which substantiates its important immunological role in vivo.

Animals↗