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Results for “immunomodulation”

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PubMed1994

The use of immunomodulators in early rheumatoid arthritis.

Immunomodulators represent a unique class of drugs that are not biologics, usually are isolated from nature, and have relatively specific noncytotoxic effects on the immune system. Although most slow-acting antirheumatic drugs (SAARDs) have effects on the immune system, these effects usually are not specific, often are cytotoxic, are not associated with specific cellular binding proteins, and their effect on immunity is difficult to correlate with their clinical effects. Most immunomodulators primarily affect T cells; because of their apparent role in rheumatoid arthritis (RA), studies of these agents are appropriate. Cyclosporine, the most widely tested of the immunomodulators, has shown significant efficacy in established RA in studies worldwide. However, only one study using cyclosporine has been performed in relatively early RA, in which the most positive effects might be expected. FK506 and rapamycin, agents similar to cyclosporine, are being tested in human transplantation; the only arthritis studies have been performed in animals. Tilomisole, imuthiol, and mycophenolate mofetil have been studied in limited RA trials, with positive effects. However, no trials have been conducted in early RA. Although promising, this class of drugs will require more studies to establish their efficacy and safety, especially in early RA.

Adjuvants, Immunologic↗

PubMed1989

The effect of immunomodulators on PHA or gamma-IFN induced release of neopterin from purified macrophages and peripheral blood mononuclear cells.

Immunomodulators cause changes in neopterin-release from purified macrophages or peripheral blood mononuclear cells by affecting the macrophage and T cell subsets activity, the intracellular cGMP/cAMP balance, or the intracellular pteridines-related biochemical pathways. Increased neopterin release was achieved by gamma-IFN or its inducers (PHA, IL-2), by interfering with the biopterin production by increased levels of cGMP or by decreasing the activity of the T suppressor cells. The released neopterin levels decreased due to decreased macrophage and T-helper cell activity or due to increased levels of cAMP. The in vitro effect of the immunomodulators has to be taken into account when assessing the neopterin levels in immunomodulators-treated patients.

Adjuvants, Immunologic↗

PubMed1994

Antiviral and immunomodulating inhibitors of experimentally-induced Punta Toro virus infections.

A major component of a US Army Medical Research and Development Command-supported program to discover and develop new drugs for the treatment of Rift Valley fever, sandfly fever, and Crimean-Congo hemorrhagic fever has been to study candidate test materials against hepatotropic infections of C57BL/6 mice induced by the related but less biohazardous Punta Toro virus (PTV). The effects of 75 compounds, some of which were considered immunomodulators in their primary mechanism of activity, were studied in the PTV infection model. Of these, ribavirin, ribamidine, ribavirin 2',3',5'-triacetate, tiazofurin, tiazofurin-5'-monophosphate, tiazofurin-2',3',5'-triacetate, selenazofurin, pyrazofurin, 3-deazaguanine, and 3-deazaguanosine were considered significantly inhibitory, acting against the infection by a direct antiviral (non-immunomodulatory) fashion. These compounds had therapeutic indices (TI) ranging from > or = 5 to 65, using increased survivors as the evaluation parameter. Immunomodulators considered significantly inhibitory to this infection were poly (ICLC), ampligen, human recombinant interferon-alpha-A/D, MVE-1, MVE-2, AM-3, AM-5, mannozym, bropirimine, CL246,738, phenyleneamine, and 7-thia-8-oxoguanosine. Utilizing increased survivor numbers as measure of activity, these inhibitors had TI ranging from > or = 16 to 1000. Other antiviral effects exerted by the active compounds included reduction of hepatic icterus, lowered serum glutamic oxaloacetic and pyruvic acid transaminases, and inhibition of recoverable serum and liver virus titers. The active immunomodulators were significantly effective when therapy was initiated as late as 48 h after virus inoculation, at a time when clinical signs of the PTV disease were being manifested in the animal.

Adjuvants, Immunologic↗

PubMed1995

Immunomodulating and antiviral activities of the imidazoquinoline S-28463.

Recently, a new class of immunomodulating agents, represented by the molecules imiquimod and R-842, has demonstrated potent antiviral and antitumor activities in animal models. In this study, another representative of this class, S-28463 (4-amino-2-ethoxymethyl-alpha,alpha-dimethyl-1H-imidazo[4,5-c]quinoline- 1- ethanol) was evaluated for its immunomodulating and antiviral activities. S-28463 induced IFN and other cytokines in vivo in mice, rats, monkeys and in vitro in human peripheral blood mononuclear cell cultures. S-28463 showed potent antiviral activity against herpes simplex virus-challenged guinea pigs when given subcutaneously, dermally, or intravaginally 24 h before infection. Antiviral activity in guinea pigs correlated with the induction of serum 2',5'-oligoadenylate synthetase activity. Thus, S-28463, like the other imidazoquinolines, demonstrates potent antiviral and immunomodulating effects in a number of models.

2',5'-Oligoadenylate Synthetase↗

PubMed1996

Effect of liposome-encapsulation on immunomodulating and antiviral activities of interferon-gamma 1.

The effect of liposome-encapsulation on the immunomodulating and antiviral activities of interferon-gamma (IFN-gamma) was evaluated in this study. The immunomodulating activity was measured by increases in phagocytic activity and in nitric oxide production by peritoneal macrophages from mice treated with both free and LIP-IFN-gamma (4000 U/mouse, intraperitoneal injection). Resident peritoneal macrophages harvested from mice treated with free unencapsulated IFN-gamma or muramyl dipeptide showed significant increases in macrophage yield, and enhanced ability to phagocytize zymosan particles. In mice treated with liposome-encapsulated IFN-gamma (LIP-IFN-gamma), both macrophage yield and phagocytic activity further increased by 2-fold over unencapsulated IFN-Y. In addition, the activation of peritoneal macrophages with LIP-IFN-gamma showed enhanced production of NO when the cells were cultured ex vivo. Using a murine respiratory influenza infection model, intranasally administered LIP-IFN-gamma conferred protection to 70% in mice challenged intranasally with 10 LD50 doses of influenza A/PR/8 virus compared with a 20% survival rate using free IFN-gamma. Together these results suggest that liposome-encapsulation increases the immunomodulating and antiviral activities of IFN-gamma. Liposome-encapsulation of IFN-gamma may provide additional therapeutic advantages by reducing IFN-gamma toxicity while prolonging its body retention.

Animals↗

PubMed1992

The role of T-cell anergy in the immunomodulation of schistosomiasis.

Schistosomes are capable of causing severe tissue damage, which results from the granulomatous inflammation that develops around the parasite eggs. Characteristic of this inflammatory process is its gradual, spontaneous down-regulation (immunomodulation) as the disease progresses. There has been general agreement that the granulomatous inflammation is a consequence of T(H)-cell-mediated delayed-type hypersensitivity to egg antigens. However, the basis of immunomodulation is less clear and has been attributed to various causes. In this review, Miguel Stadecker proposes a novel mechanism of immunomodulation based on the observation that accessory cells from schistosome-infected individuals are capable of inducing a state of unresponsiveness or energy in a subpopulation of antigen-specific CD4(+) T(H)-cell clones identified with delayed-type hypersensitivity reactions.

Journal Article↗

PubMed1993

Effect of immunomodulators pyrimethamine and cimetidine on immunosuppression induced by sulfur mustard in mice.

Despite extensive world-wide research no effective therapy has been devised for the treatment and cure of patients exposed to sulfur mustard (S-M). A severe suppression of the immune system still remains the major cause of opportunist infections, septicemia and death in patients injured by S-M. In this report we present a model of S-M contamination in mice which is suitable for immunomodulation studies. Results show that differing doses of S-M caused an overall suppression of the immune response to SRBC as indicated by agglutination titers, (DTH) tests, spleen histology and spleen weight indices. In the second stage two immunomodulating agents; pyrimethamine and cimetidine were employed and their effectiveness in augmenting immune responses after S-M induced immunosuppression was evaluated. Pyrimethamine, at all doses employed, enhanced antibody titers to SRBC, augmented DTH responses, and restored splenic follicles as compared with controls only exposed to S-M. Cimetidine augmented antibody titers and enhanced DTH responses at doses of 10 and 15 mg/kg as compared with controls. At a dose of 5 mg/kg cimetidine did not exhibit any effect on titers or DTH responses. Histological studies revealed that cimetidine restored splenic follicles and increased macrophage numbers and phagocytic activity at all three doses. Spleen weight indices were not augmented by either drug. These data provide evidence that immunomodulating drugs may prove effective in countering the immunosuppressive effects of S-M.

Animals↗

PubMed1993

Immunomodulating activities of orally administered SMANCS, a polymer-conjugated derivative of the proteinaceous antibiotic neocarzinostatin, in an oily formulation.

Immunomodulatory effects of oily formulated SMANCS, a polymer conjugated derivative of the proteinaceous antibiotic neocarzinostatin, after oral administrations to mice was investigated. The oral administrations of SMANCS, dissolved in medium-chain triglyceride containing phosphatidylcholine and polyglycerine dioleate (oily SMANCS), resulted in: (1) augmentation of NK cell activity in naive mice, (2) activation of macrophage cytostasis in naive mice, (3) enhancement of the generation of cytotoxic T-lymphocytes in mice immunized with allogeneic lymphocytes, (4) production of circulating interferon in naive mice, and (5) increase of delayed-type hypersensitivity response in mice immunized with sheep red blood cells. The degree of immunomodulation orally stimulated with oily SMANCS was similar to that of the immunomodulation induced by i.v. or i.p. administrations of aqueous formulated SMANCS (aqueous SMANCS). Although SMANCS is a protein drug that may be digestable by various enzymes present in the stomach, in the present study immunomodulating activities of SMANCS were clearly demonstrated when an oily formulation of the compound was administered to mice orally. Since aqueous SMANCS administered parenterally and oily SMANCS administered orally exhibit the same immunomodulatory activities and the former has demonstrated antitumor activity in man and animals, the latter may possess this same antitumor activity.

Adjuvants, Immunologic↗

PubMed1994

Comparison of immunomodulative effects of histamine-2 receptor antagonists in gastric cancer patients: focus on the lymphoblastogenesis and cytotoxicity of peripheral blood mononuclear cells.

A proposed mechanism of the immunomodulative effects of histamine-2 receptor antagonist (H2-RA) has been considered to be the inhibition of suppressor T-lymphocyte activity, an increase in interleukin-2 production of helper T-lymphocytes, and an enhancement of natural killer cell activity. Since there is a lack of comparative data about the immunomodulative effects of various H2-RAs, cimetidine, ranitidine and famotidine on peripheral blood mononuclear cells (PBMC), study of the comparison of the actions of H2-RA will be required. We compared the immunomodulative effect of each H2-RA on PBMC in patients with gastric cancer. DNA synthesis, cytotoxicity of PBMC against K562 cells and gastric cancer cell lines, and the levels of supernatant soluble interleukin-2 receptor (sIL-2R) were measured after the addition of each H2-RA, respectively. Increased suppressor cell activities were attenuated and restored to the levels of normal controls by the addition of cimetidine to H2-RA. Statistically significant lymphoblastogenesis and cytotoxicity against K562 cells were observed only in cimetidine-treated PBMC (P < 0.05). Such effects were not observed in ranitidine- or famotidine-treated PBMC. Neither cimetidine- nor ranitidine-activated activated PBMC showed any significant cytotoxicity against gastric cancer cells. Significantly increased levels of sIL-2R were found in supernatants obtained from culture flasks treated with cimetidine or ranitidine and phytohemagglutinin (P < 0.01). A significant correlation was found between the cytotoxicity of cimetidine- or ranitidine-treated PBMC and supernatant sIL-2R (P < 0.05). In conclusion, the most strongly modulative substance among H2-RAs was cimetidine and the least modulative drug was famotidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗

PubMed1996

The current status of extracorporeal immunomodulation.

A course of extracorporeal immunomodulation is defined as a treatment which intervenes and consequently modulates or, in other words, activates and/or suppresses the immune mechanisms utilizing an extracorporeal procedure. Such treatment has traditionally depended on administration of drugs, typically steroids and/or immunosuppressants. Most of the apheresis techniques currently available belong to or are very similar to those used for blood purification and involve the removal of the pathogenic substances such as antibody(ies) and/or immune complex(es). The cellular components are also treated in extracorporeal immunomodulation. As some of the extracorporeal immunomodulation techniques have already demonstrated clinical effectiveness that cannot be achieved by conventional therapies, it is appropriate to propose a new therapeutic approach to the immunological disorders.

Blood Component Removal↗

PubMed2005

Aqueous exposure to Aroclor 1254 modulates the mitogenic response of Atlantic salmon anterior kidney T-cells: indications of short- and long-term immunomodulation.

Polychlorinated biphenyls (PCBs) exist as persistent organic pollutants in numerous river systems in the United States. Unfortunately, some of these rivers are sites of active Atlantic salmon restoration programs, and polychlorinated biphenyls have been implicated as ancillary factors contributing to failed salmon restoration. Here, we investigate the immediate and chronic effects of intermediate duration aqueous PCB exposure (1 or 10 microgL-1 Aroclor 1254) on the mitogen-stimulated lymphoproliferative response of Atlantic salmon anterior kidney leukocytes (AKLs). A short-term study was designed to examine immunomodulation in Atlantic salmon smolts immediately following 21 days of aqueous exposure, while a long-term study evaluated chronic impacts in the mitogen response in parr 15 months post-exposure as larvae. The proliferative response of AKLs to the mitogens concanavalin A (CON A), phytohemaglutinnin-P (PHA-P), pokeweed mitogen (PWM), and lipopolysaccharide were used as an indice of immunomodulation. The proliferative response to the T-cell mitogens CON A and PHA-P was significantly increased in the 10 microgL-1 group (n=10; P=0.043 and 0.002, respectively) immediately following exposure of smolts. Additionally, The PHA-P response was significantly increased in the 1 microgL-1 exposure group (n=10, P=0.036). In fish treated as larvae and tested 15 months later, the PHA-P sensitive populations exhibited elevated proliferation in the 1 and 10 microgL-1 groups (n=12, P<0.04) relative to the vehicle control while the PWM response was significantly increased (n=12, P=0.036) only in the 10 microgL-1 treated groups. These results demonstrate an immunomodulatory effect of PCBs on T-cell mitogen sensitive populations of lymphocytes in Atlantic salmon as well as long-term immunomodulation in PHA-P and PWM sensitive populations.

Analysis of Variance↗

PubMed2004

Co-administration of immunomodulator tuftsin and liposomised nystatin can combat less susceptible Candida albicans infection in temporarily neutropenic mice.

In order to develop a prospective chemotherapeutic agent against opportunistic infections, it is important to know that host factors such as degree of immunological debility as well as recovery of immune functions to normality may contribute significantly to a successful elimination of the pathogens. We demonstrated previously that concomitant delivery of antimicrobial agents and immunomodulators to the pathogen harbouring-host contributes to the complete elimination of the deep-seated fungal infections (aspergillosis and candidiasis) in animals with normal immune status. Considering that neutropenic hosts are the main targets of such infections, it can be argued about the potential of the immunomodulator-based therapy in subjects with non-functional immune system. To resolve the hypothesis, we studied the role of immunomodulator tuftsin against experimental murine candidiasis in temporarily neutropenic Balb/c mice. The neutropenic mice were challenged with an isolate of Candida albicans that was showing less susceptibility to both free and liposomised-amphotericin B. The co-administration of tuftsin increased the efficiency of liposomised-polyene antibiotics (nystatin and amphotericin B) against experimental murine candidiasis in immunocompromised Balb/c mice. Pretreatment with liposomised tuftsin prior to C. albicans infection clearly enhanced protection against candidiasis, suggesting a prophylactic role of tuftsin in normal and temporarily neutropenic animals.

Adjuvants, Immunologic↗

PubMed2006

Evaluation of immunomodulation by Lactobacillus casei Shirota: immune function, autoimmunity and gene expression.

Lactic acid bacteria are claimed to have immunomodulating effects. Stimulation as well as suppression of T helper (Th)1 mediated immune responses, have been described for various strains. Experiments involving Lactobacillus casei Shirota (LcS) detected mainly enhancement of innate immune responses and promotion of Th1 mediated immune reactivity. To confirm and further investigate modulation of Th1 responses and development of autoimmune disease by LcS, the consequences of oral administration of LcS were assessed in several experiments. The effect of LcS varied between the different models. No modulation was found in the mitogen-induced cell proliferation and cytokine release assays in mesenteric lymph nodes of Wistar rats. LcS inhibited the Th1 mediated immune response in an adapted murine Local Lymph Node Assay (LLNA) in BALB/c mice, whereas experimental autoimmune encephalomyelitis (EAE) in Lewis rats was aggravated. These varying effects on Th1 responses indicate that beneficial as well as harmful effects on immune related disorders could occur after LcS consumption. Since microarray analysis is suggested to be more sensitive and predictive than functional tests, gene expression profiling was included as an alternative endpoint in the testing of immunomodulation. The detected gene expression profiles did not reflect the effects of LcS on the immune system. Microarray analysis may therefore have no more predictive value than immune function assays when investigating immunomodulation by probiotics. To gain further insight into effects of probiotics on immune function, experiments including cytokine assays and gene expression analysis combined with disease models could be useful.

Animals↗

PubMed2006

Enhancement of Th2 responses to replicative herpes simplex virus type 1 vectors by immunomodulative chemotherapy.

Replicating, neuroattenuated gamma(1)34.5-deleted herpes simplex virus (HSV)-vectors are tools for experimental therapy of gliomas and autoimmune diseases. Immunomodulative treatment with Linomide (quinoline-3-carboxamide) has earlier been shown to facilitate some virus infections and reduce autoimmunity. Now we aimed at elucidating the safety of immunomodulatory therapy during infection of mice with HSV vectors. We focused on immunological and virological changes in the nervous system. BALB/c mice were infected intranasally with the HSV-1 recombinant viruses R3616, R3659 and R8306 (with mouse IL-4 transgene) and either treated with Linomide or left untreated as control groups. Treatment with Linomide was started 7 days before infection. Virological analysis consisted of viral culture and PCR for HSV DNA. Cytokine responses were studied with quantitative RT-PCR and EIA. Immunomodulatory treatment did not change the clinical course of infections. The expression of IL-4 and IL-10 in brains increased in Linomide-treated mice, particularly in infection with R8306. The expression of IL-23p19 was decreased in brains in Linomide-treated, vector-infected mice, in comparison with nontreated but virus-infected animals. Immunomodulatory treatment did not increase the viral load in brains in any of the mouse groups infected with R3616, R3659 or R8306. Immunomodulative treatment with Linomide did not compromise the safety of replicating HSV-vectors, not even the one with IL-4 transgene, suggesting that combination of immunomodulation with virotherapy may be beneficial in the treatment of certain diseases of the central nervous system. Further investigations are needed to elucidate the effects of immunomodulatory therapy in order to improve vector survival and efficacy of gene therapy.

Adjuvants, Immunologic↗

PubMed2005

Immunomodulation with human recombinant autoantigens.

The loss of beta cells in type 1 diabetes is the consequence of a T cell-dependent autoimmune attack. Autoantibodies against GAD65 (Mr 65.000 isoform of glutamic acid decarboxylase), IA-2 (insulinoma-associated protein IA-2) or insulin, alone or in combination, predict disease. Preclinical studies in spontaneously diabetic rodents suggest that immunomodulation with autoantigens might alter the course of autoimmune diabetes. Oral insulin reduces the development of diabetes in risk subjects with high insulin autoantibody levels. Giving alum-formulated GAD65 to patients classified with latent autoimmune diabetes of the adult (LADA) is safe and suggests possible immunomodulating effects of GAD65. Future immunomodulation trials might better ascertain subjects based on HLA genetic risk factors, the level of insulin that is still produced or by combining autoantigens with, for example, anti-CD3 antibodies, to induce antigen-specific tolerance and thereby a long-lasting protection for beta cells.

Animals↗

PubMed2006

Immunomodulators as an antimicrobial tool.

The spectrum of infectious diseases has shifted in the past 50 years to include those caused by microbes that cause disease predominantly in immunocompromised individuals. This phenomenon has underscored the dependence of microbial virulence on the immune status of the host. The limited efficacy of the available antimicrobial armamentarium in immunocompromised individuals, combined with increasing resistance to these agents, has led to an urgent need for new therapies for infectious diseases. Immunomodulation represents a novel approach to antimicrobial therapy that depends on bolstering host immunity, rather than direct antimicrobial activity. Immunomodulators can be divided into those that are specific to pathogens (pathogen-specific) and those that are not specific to pathogens (non-specific). However, to date only a few immunomodulators have been evaluated for their efficacy as antimicrobial tools.

Anti-Inflammatory Agents↗

PubMed2002

Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice.

Peroxisome proliferators (PPs) are a large class of structurally diverse chemicals, which includes drugs designed to improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin-resistance and atherosclerosis. We have recently demonstrated that exposure of rodents to potent PPs indirectly causes a number of immunomodulating effects, resulting in severe adaptive immunosuppression. Since the peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in mediating the pleiotropic responses exerted by PPs, we have compared here the immunomodulating effects of the PPs perfluorooctanoic acid (PFOA) and Wy-14,643 in wild-type and PPARalpha-null mice. The reductions in spleen weight and in the number of splenocytes caused by PP treatment in wild-type mice was not observed in PPARalpha-null mice. Furthermore, the reductions in thymus weight and in the number of thymocytes were potently attenuated in the latter animals. Similarly, the dramatic decreases in the size of the CD4(+)CD8(+) population of cells in the thymus and in the number of thymocytes in the S and G2/M phases of the cell cycle observed in wild-type mice administered PPs were much less extensive in PPARalpha-null mice. Finally, in contrast to the case of wild-type animals, the response of splenocytes isolated from the spleen of PP-treated PPARalpha-null mice to appropriate T- or B-cell activators in vitro was not reduced. Altogether, these data indicate that PPARalpha plays a major role in the immunomodulation caused by PPs. The possible relevance of these changes to the alterations in plasma lipids also caused by PPs is discussed.

Adjuvants, Immunologic↗

PubMed1989

Combined therapeutic effects of conventional agents and an immunomodulator, PSK, on rat prostatic adenocarcinoma.

Growth alteration effects of an immunomodulator, PSK, were investigated individually and in association with conventional chemotherapeutic agents cyclophosphamide, cisplatin and fluorouracil in an experimental prostatic cancer model. Copenhagen rats had subcutaneous tumors induced by injections of cells cultured in vitro from a highly metastatic hormonally unresponsive subline of the Dunning rat prostatic tumor, MAT-LyLu. Treatment with conventional agents and the immunomodulator agent individually and in combination began three days after tumor cell inoculation. PSK used alone was not able to significantly influence tumor growth. In appropriate doses, each conventional agent significantly retarded tumor growth. Used in combination, PSK and conventional agents retarded tumor growth locally and decreased metastatic spread of the tumor. Animals receiving combination therapy had increased life spans over those animals receiving single standard chemotherapeutic agents. Immunomodulation with PSK may enhance the antineoplastic effects of chemotherapeutic agents and offer a treatment option for hormone resistant prostatic cancer.

Adjuvants, Immunologic↗