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Caprine serum fraction immunomodulator as supplemental treatment of lower respiratory disease in the horse.

Suppurative lower airway disease is a common debilitating disease in performance horses and, while rarely fatal, is often recalcitrant to conventional therapy. A variety of treatments have been used to combat this condition and we conducted two types of studies to determine if caprine serum fraction--immunomodulator (CSFI), a nonspecific immunomodulator, improved recovery from lower respiratory disease. Two dose response studies were performed to ascertain the efficacy of CSFI. Horses were maintained daily on conventional antibiotic therapy. Respiratory tract exudate, nasal discharge, dyspnoea, chest auscultation and cough frequency were monitored weekly. One hundred percent of the horses treated with 2 i.m. injections of either 60 or 120 mg CSFI one week apart showed significant improvement with each weekly evaluation and were fully recovered by week 3. Horses treated with 15 or 30 mg CSFI did not differ significantly from the control group. Only 10% of the control horses responded to conventional antibiotic therapy. An expanded field trial utilising 80 horses diagnosed with lower respiratory disease and housed at 4 equine clinics was conducted. Thirty-five percent of the 40 control horses, treated solely by conventional antibiotic therapies, recovered while 75% of the horses treated with a supplemental administration of 60 mg CSFI as described above recovered. The combined data from these studies showed that CSFI was able to promote an overall recovery from lower respiratory disease of 86%.

Adjuvants, Immunologic↗

Immunomodulating agents and hepatic drug-metabolizing enzymes.

Immunomodulating agents are increasingly used in clinical practice to alter the course of various malignancies, autoimmune diseases, or immunodeficiencies. Experimental data obtained in laboratory animals suggest that nearly all agents available today are likely to inhibit hepatic drug-metabolizing enzymes. Although further investigation is warranted, a direct stimulation of the reticuloendothelial system is likely to play a key role. Potentially severe drug interactions are the main clinical consequences to be considered, particularly in the field of cancer chemoimmunotherapy and vaccination. Besides immunomodulating agents, drugs with the toxic potential for immunoenhancement may also be considered in that respect.

Adjuvants, Immunologic↗

Role of calcium in biphasic immunomodulation by gamma-HCH (lindane) in mice.

gamma-HCH (Lindane) is reported to cause a biphasic immunomodulation-stimulation followed by suppression-after oral administration in mice. Role of calcium in this biphasic immunomodulation was assessed after 4, 12 and 24 wks of gamma-HCH administration. 45Ca-uptake was enhanced during the initial immunostimulation followed by decrease concomitant with immunosuppression. Lymphocyte proliferation was inhibited during both the phases of immune response by verapamil, a calcium channel blocker, and by trifluoperazine, a calmodulin inhibitor. These findings show an impairment of calcium homeostasis in lymphocytes culminating into the biphasic immunomodulatory effects of gamma-HCH.

Adjuvants, Immunologic↗

Immunomodulating effect of met-enkephalin on different stages of lymphocyte proliferation induced with concanavalin A in vitro.

Met-enkephalin (ME) in the range of concentrations 10(-15) M to 10(-9) M has exhibited an immunomodulating effect on concanavalin A (Con A) induced proliferation of mice lymphocytes from lymph nodes in vitro. The effect of ME was shown to vary with the stage of lymphocyte activation and to depend on the mitogen dose. In the case that ME and Con A were injected simultaneously, at the zero time of proliferation, maximum inhibition was observed on the first and fourth days. In an other set of experiments when ME was added at intervals of 4 hours before measuring the proliferation response value, both inhibition (after 24 hours of proliferation) and stimulation (after 28 and 96 hours) were observed. Opioid ligands of various classes were found to act in the same manner as ME. Naloxone was shown to block the immunomodulating effect of opioids.

Animals↗

Immunostimulatory activity of Milife, a novel immunomodulator of fungus origin.

Milife is a novel immunomodulator derived from the fungus Fusarium Sambucium. In this study we examined immunomodulatory properties of Milife in 10 months-old BLRB mice. Milife was given to mice orally in a daily dose of 1 mg per mouse, for 2 to 6 days. Groups of mice were sacrificed on days 2, 4, and 6 of treatment, and 3 weeks after completion of a 6 days treatment with Milife, and lymphoid organs were obtained for analysis. Milife administration led to rapid and significant increase in total leukocyte and lymphocyte numbers in peripheral blood that persisted for at least 3 weeks after a 6 days treatment. Cellularity of lymph nodes, bone marrow and thymus increased significantly at days 4 and 6 of treatment, but returned to pretreatment levels after Milife discontinuation. Though total splenocyte numbers did not change dramatically, there occurred delayed increase in CD4+ cells in the spleen 3 weeks following treatment. Preferential accumulation of CD4+ cells was also consistently found in peripheral blood, with the peak being observed at day 6 of treatment. As a result, CD4/CD8 ratio in blood and spleen was significantly higher in treated than in untreated mice. Splenocytes from treated mice proliferated more vigorously in response to Con A. When added in vitro, Milife also mildly costimulated Con A-induced proliferation of splenocytes from intact animals. In conclusion, we have found that Milife can stimulate leuko- and lymphopoesis in BLRB mice, in particular, accumulation of CD4+ T cells in peripheral lymphoid organs. We conclude that Milife may represent an immunomodulator with the potential to correct T cell dysfunction in patients with immunodeficiency.

Adjuvants, Immunologic↗

Biodegradable nanocapsules containing a lipophilic immunomodulator: drug retention and tolerance towards macrophages in vitro.

Nanocapsules (250 nm diameter) were prepared from poly (D, L-lactide) containing a lipophilic immunomodulator: MDP-L-alanyl cholesterol (MTP-Chol). High encapsulation rates were obtained at 37 degrees C in culture medium or in buffers imitating phagosomes and lysosomes. The tolerance of these particles by rat alveolar macrophages in vitro was tested. A slight toxicity was observed which was the result of two factors: the capacity of the immunomodulator to stimulate the generation of nitrite oxide by the L-arginine-dependent pathway and the polymer itself. The latter toxicity seemed to be mediated by a different mechanism.

Acetylmuramyl-Alanyl-Isoglutamine↗

Regulation of murine airway eosinophilia and Th2 cells by antigen-conjugated CpG oligodeoxynucleotides as a novel antigen-specific immunomodulator.

The characteristic features of bronchial asthma reflect the orchestrated activity of Th2 cells. Oligodeoxynucleotides containing CpG motifs (CpG) have recently been highlighted as an immunomodulator that biases toward a Th1-dominant phenotype. We have previously reported that intratracheal coadministration of CpG and allergen inhibited airway eosinophilia and hyperresponsiveness in a synergistic manner. To substantiate the synergism between CpG and Ag, we introduced a covalently linked conjugate between CpG and Ag and examined the efficacy on airway eosinophilia and Th2 cytokine production. We found that the conjugated form of CpG plus Ag was 100-fold more efficient in regulating airway eosinophilia than the unconjugated mixture. The inhibitory effects lasted for at least 2 mo. The inhibition of airway eosinophilia by the conjugate was Ag specific and associated with an improvement of the airway hyperresponsiveness and the unresponsiveness of the Ag-specific Th2 cells in the regional lymph nodes. The CpG-Ag conjugate was 100-fold more effective than the unconjugated mixture for inducing in vitro Th1 differentiation in an IL-12-dependent manner. Our data show that CpG conjugated to Ag can work as a novel Ag-specific immunomodulator and imply that inhalation of allergen-CpG conjugate could be a desensitization therapy for patients with bronchial asthma.

Adjuvants, Immunologic↗

NIH conference. Immunomodulators in clinical medicine.

A major difficulty limiting the use of immunomodulators in clinical medicine has been the complexity of the immunoregulatory network in which modulation of one component usually perturbs the entire system, thus diminishing the specificity of the approach. Lymphokine-activated killer cells infused with interleukin-2 have proved effective in inducing remissions in several advanced cancers, particularly metastatic renal cell carcinomas. The interferons have shown direct antiproliferative effects as well as specific effects on immune function. Alpha-interferon has shown impressive antitumor effects in hairy cell leukemia and significant antiviral effects in papillomavirus infection of the genital tract. Interleukin-2 has multifaceted effects on various limbs of the inflammatory and immune responses and may be the critical common denominator in the adjuvant effects of several other compounds. Monoclonal antibodies have assumed an increasing role in diagnostic and therapeutic approaches to neoplastic and immune-mediated diseases. Finally, several immunomodulators are currently being tested in the treatment of the immune defect of the acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗

[Interferon inducers: new generation of immunomodulators].

Interferon (IFN) inducers are the agents having a wide range of antiviral activity. They have not only etiotropic, but marked immunomodulating effects. INF inducers different in its nature cause IFN synthesis in different immunocytic populations. The kinetics of the production of IFN and their antigenic composition depend on the chemical structure of an inducer and on their stimulated target cell populations. Their capacity of stimulating the synthesis of IFN in these or those organs determines the spectrum of application of an inducer and the time course of serum IFN accumulation--the strategy of its use. IFN inducers have a number of advantages over exogenous IFN. They stimulate the synthesis of the body's own IFN, which has no antigenicity unlike the most widely used recombinant IFN. IFN inducers cause IFN circulation at the therapeutical levels, at the same time to achieve such an effect requires multiple administration of large-dose exogenous agents. Some IFN inducers includes IFN synthesis in particular cell populations and organs, which has certain advantages over the polyclonal stimulation of IFN immunocytes. IFN inducers are well combined with IFN and other antiviral agents. The combination of these properties leads to the conclusion that IFN inducers are a highly promising group of agents having both etiotropic and immunomodulating effects.

Adjuvants, Immunologic↗

Immunomodulative effects of some drugs of abuse on human peripheral blood lymphocytes.

The cytotoxic effects of opiates, cocaine and their metabolites on peripheral blood mononuclear cells from healthy volunteers, concerning cell viability, were studied in a wide range of concentrations (ranging from 10-(2) to 10-(8) M), by 2 colorimetric in vitro assays, the neutral red uptake assay and thiazolyl blue tetrazolium bromide assay. All tested drugs of abuse and their metabolites were non-cytotoxic at concentrations lower than 10-(5) M. The possible immunomodulative effects of these substances were evaluated through phytohemagglutinin-induced lymphocyte proliferation ([3H]-thymidine DNA incorporation assay) as well as by a 51Cr release natural killer assay. The results showed immunomodulative effects of all the opiates tested. Cocaine, freebase cocaine and benzoylecgonine produced a statistically non-significant decrease of phytohemagglutinin proliferation. Cocaine induced a statistically non-significant increase, whereas freebase cocaine and benzoylecgonine showed a non-significant decrease of natural killer cell activity.

Adult↗

Efficacy and mode of action of an immunomodulator herbal preparation containing Echinacea, wild indigo, and white cedar.

Using the example of an allopathic herbal combined preparation containing Echinacea root, wild indigo root, and white cedar leaf tips (Echinaceae radix + Baptisiae tinctoriae radix + Thujae occidentalis herba = Esberitox N), the efficacy and mode of action of a phytoimmunomodulator, or immune system enhancer, is described. Efficacy of the immunomodulator has been demonstrated in studies of acute viral respiratory tract infections and infections requiring antibiotic therapy. In a recent study compliant to GCP, the therapeutic superiority of the herbal immunomodulator over placebo was confirmed as statistically significant and clinically relevant. The present overview describes a model of the antigen-independent mode of action of phytoimmunomodulation ("immunobalancing").

Adjuvants, Immunologic↗

Immunomodulating therapy with rIL-2 and interferon alpha-induces in vivo expression of Bcl-2, Fas (APO-1/CD95), and Fas ligand on peripheral lymphocytes (a pilot study).

The first Phase I Trial with a combination of IL-2 and IFN-alpha was published in 1989. There are still some questions though, concerning the in vivo effects of this combination on lymphocytes. We designed a prospective pilot study to evaluate in vivo effects of low dose IL-2 and IFN-alpha combination on expression of Bcl-2, FAS (Apo-1/CD 95), Fas Ligand, IL-2 receptor (CD25), and HLA-DR on peripheral lymphocytes in patients with advanced renal cell carcinoma. After initiation of the immunomodulating therapy, Bcl-2 expressing lymphocytes increased significantly on day 3 (p < 0.025), Fas (Apo-1/CD95) expressing lymphocyte increased significantly on day 5 (p < 0.003), Fas ligand expressing lymphocytes increased significantly on day 3 (p < 0.004), HLA-DR expressing lymphocytes increased significantly on day 5 (p < 0.003), and IL-2 receptor (CD25) expressing cells increased significantly on day 5 (p < 0.01). We conclude that immunomodulating therapy induces in vivo expression of Bcl-2, Fas (Apo-1) and Fas Ligand in lymphocytes significantly.

Adjuvants, Immunologic↗

Therapy of human pancreatic carcinoma implants by irinotecan and the oral immunomodulator JBT 3002 is associated with enhanced expression of inducible nitric oxide synthase in tumor-infiltrating macrophages.

We determined the therapeutic effect of irinotecan (CPT-11) combined with the immunomodulator JBT 3002, a synthetic bacterial lipopeptide (N-acylated derivative of psi-amino-C1-C3-alkane-sulfonic acid), against highly metastatic human pancreatic carcinoma cells injected into the pancreas of athymic nude mice. Mice received four courses consisting of three daily oral doses of JBT 3002, followed by once weekly i.p. injection of CPT-11. Control mice were treated with CPT-11 alone, JBT 3002 alone, or saline. Tumor growth and metastasis were assessed by gross pathology and confirmed by histological examination. Treatment with CPT-11 alone significantly decreased the median volume of pancreatic tumors and the incidence of metastasis, whereas treatment with only JBT 3002 did not. The combination therapy of CPT-11 plus JBT 3002 decreased tumor volume and incidence of metastasis significantly more than CPT-11 alone. The number of apoptotic cells (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), the number of scavenger-receptor-positive macrophages, and expression level of inducible nitric oxide synthase (iNOS) within lesions directly correlated with therapeutic effects. Indeed, the in vitro incubation of tumor cells with macrophages activated by JBT 3002 plus IFN-gamma produced a significant lysis of tumor cells that could be blocked by a specific inhibitor of iNOS. Collectively, these data demonstrate that the oral administration of the immunomodulator JBT 3002 combined with i.p. injection of CPT-11 can decrease the growth of human pancreatic carcinoma and the incidence of metastasis in nude mice by both a direct antitumor effect and the activation of iNOS in infiltrating macrophages.

Adjuvants, Immunologic↗

[The immunomodulating and antitoxic properties of preparations of lipopolysaccharides from representatives of the genus Francisella].

The study of the biological properties of lipopolysaccharides (LPS) of bacteria of the genus Francisella (F. tularensis, F. novicida, F. novicida-like, F. philomiragia) revealed that the preparation of Francisella LPS possessed immunomodulating and antitoxic properties in the absence of toxicity. At the same time the structure of LPS (S or R) was found to produce an essential effect of the immunobiological activity of this molecule. Thus, the S-forms of LPS proved to be more effective as immunomodulators and the R-forms of LPS, as antagonists of classical endotoxins.

Adjuvants, Immunologic↗

Cytotoxic and immunomodulative effects of flunitrazepam, zipeprol and trihexyphenidyl on human peripheral blood lymphocytes.

The cytotoxic effects of flunitrazepam, zipeprol and trihexyphenidyl on cell viability of peripheral blood mononuclear cells from healthy volunteers were studied at concentrations from 10(-2) to 10(-8) M by 2 colorimetric in vitro assays: the neutral red uptake assay and thiazolyl blue tetrazolium bromide assay. All tested drugs of abuse were non-cytotoxic at concentrations lower than 10(-5) M. Possible immunomodulative effects of these substances were evaluated through phytohemagglutinin induced lymphocyte proliferation ([3H]-thymidine DNA incorporation assay) and by a 51Cr release natural killer assay. The 3 drugs studied produced statistically significant immunomodulative alterations on both immunological parameters.

Adjuvants, Immunologic↗

[Immunomodulating effects of vitamin K preparations and its potentiation by riboxine in acute cold stress].

The vitamin K preparations phylloquinone, menadione, and vikasol produce an immunomodulant effect under acute cold-induced stress conditions. A combination of phylloquinone, menadione and riboxin provides an effective means of correcting the immunological reactivity and antioxidant state under the conditions of immersion cooling. The immunomodulant effect of naphthoquinones and riboxin is correlated with their antioxidant activty.

Acute Disease↗

[Comparative in vitro study of the effectiveness of various immunomodulating substances in tick-borne encephalitis].

Suppressing effect of tick-borne encephalitis (TBE) virus on expression of lymphocyte subpopulation receptors has been demonstrated in vitro. Effects of 14 immunomodulators on expression of T lymphocyte receptors under the effect of TBE virus have been compared. Anti-TBE immunoglobulin, 4-iodantipyrin, and leukinferon had the highest protective effect after a preventive injection. Thymalin and leukinferon in combination with human leukocytic interferon were the most effective within the treatment protocols. Further studies of sensitivity of immunoregulator cells to immunomodulators is recommended with the aim of adding these drugs to therapy of TBE patients.

Adjuvants, Immunologic↗

[Guiding-evaluation of immunomodulating activity of the Liuwei Dihuang Decoction during the stepwise fractionation].

OBJECTIVE: To conduct the activity evaluation for immunomodulating components from the Liuwei Dihuang Decoction (LWDHD). METHODS: Cyclophosphamide (Cy)-treated mice were used as the immunodeficient model and the antibody production response in plaque-forming cell (PFC) assay was employed as the activity-evaluating parameter. Stepwise fractionation was guided by activity-evaluation. RESULTS: Fr1, the ethanol-soluble fraction, and Fr2, the ethanol insoluble fraction of LWDHD, both significantly improved the antibody production response in Cy-treated mice, in which Fr2 showed stronger activity than that of Fr1. Fr2 was further fractionated. Fr2-CA4, one of the fractions obtained by active carbon chromatography from Fr2, exhibited the strongest activity in comparison with other fractions. CONCLUSION: CA4, which is mainly composed of acidic polysaccharides, is the main immunomodulating active fraction contained in the ethanol-insoluble fraction of LWDHD.

Adjuvants, Immunologic↗