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In this review we delineate the rationale for immunotherapy in multiple sclerosis and describe the various levels at which immune intervention, according to a modern model of the immune system organization, is feasible. Current and future immunosuppressive and immunomodulating therapeutic approaches at the level of antigen presentation and at the lymphocyte and cytokine network levels are discussed.
The immunomodulating action of two mushroom antitumor polysaccharides, polysaccharide-protein complex (PSPC) and lentinan, was elucidated through analysing the expression profile of cytokines during a time course (0 h to 48 h) after their administration. Among the 5 cytokine genes, the induction of a marked increase in the mRNA levels of IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma and M-CSF by PSPC and lentinan was observed in the peritoneal exudate cells and splenocytes. However, the time point of their increased production was different after PSPC and lentinan administration.
Advances in the understanding of genetic engineering, protein expression, and Ig function have come together to allow for the rapid synthesis and production of a novel generation of potent immunomodulating reagents. Selective approaches that allow the isolation of desired specificities will be elucidated through meticulous engineering techniques. This, in turn, may eventually result in the fulfillment of the tremendous potential of engineered proteins for therapeutic and diagnostic applications.
The lethality and distribution of rabies virus were evaluated in swiss mice experimentally infected with street rabies virus, vaccinated and submitted to immunomodulation by P .acnes (formerly Corynebacterium parvum). The animals were sacrificed at different times,when the different tissues were collected and submitted to fluorescent antibody test (FAT) and mouse inoculation test (MIT). The group submitted to vaccination and P. acnes treatment presented a percentage of survival superior to that observed in infected mice only treated with P. acnes. Control infected animals had the lowest survival rates. The distribution of rabies virus in spleen of infected mice, vaccinated and submitted to P. acnes was superior to that verified in infected mice not treated with P.acnes. The increased survival correlated with the distribution of rabies virus in lymphoid tissues, could be interpreted as the consequence of P. acnes activity on macrophages. The results suggest the role of macrophages against rabies virus infection in mice and the importance of vaccination in the post expositive treatment of rabies.
Responses of vaccination and treatment to immunomodulators against rabies in mice were evaluated through macrophage inhibition factor (MIF), intra-pad inoculation (IPI) and serum neutralization (SN) tests and by the detection of gamma-interferon (IFN-gamma). Onco-BCG, Avridine and Propionibacterium acnes were administered to groups of mice. Higher survival rates were found in animals treated with P. acnes. Lower levels of IFN-gamma were observed in the groups of infected and vaccinated mice. The IPI was not effective on detecting the response of delayed-type hypersensitivity. Vaccine induced in the infected animals a more intense response to MIF reaction.
The natural killer (NK) activity and lethality were evaluated in swiss mice experimentally infected with street rabies virus and submitted to immunomodulation by P. acnes (formerly Corynebacterium parvum). The infected animals were sacrificed at different times and spleen non-adherent cells were obtained through ficoll-hypaque gradient and depletion of glass-adherent cells. Immunosuppression was observed in rabies virus infected mice correlated with lower NK activity in clinically ill animals. Higher NK activity and percentual of survival were observed in the group submitted to P. acnes. The increased survival correlated with higher NK activity induced by P. acnes suggests a protective role of this natural barrier against rabies virus infection in mice.
Three experiments have been carried out to verify the effectiveness of an immunomodulator, Baypamun (Bayer AG) in limiting the spread of Bovine herpesvirus-1 (BHV-1), the causal agent of infectious bovine rhinotracheitis (IBR). In the first experiment, four calves infected with BHV-1 developed severe disease whereas four calves given Baypamun simultaneously with the virus had less severe disease. Four other calves in contact with the infected calves became severely ill but another four given Baypamun were only mildly affected. In the second experiment three calves infected with BHV-1, which reacted with typical disease, were allowed to remain in contact with six calves. All six calves were given Baypamun at various times following the exposure to BHV-1 infection and all showed a much reduced reaction with two treated for 4 days developing no clinical disease. Finally, in the third experiment one calf vaccinated one month before the start of the experiment did not develop any signs of disease when housed together with a calf experimentally infected with BHV-1. Of four other calves, vaccinated when the infected calf showed the first signs of disease, only the two given Baypamun in addition to the vaccine, were protected from clinical disease whereas the two given vaccine only developed classical signs of IBR. In the three experiments the virus shedding by the Baypamun-treated calves resulted to be significantly reduced.
Rheumatoid arthritis (RA) is a chronic disease affecting 0.8% of the population. Nonsteroidal anti-inflammatory drugs reduce the pain and inflammation of RA and improve mobility but do not slow the progression of joint damage. Disease-modifying antirheumatic drugs (DMARDs), which limit potentially irreversible joint damage, may influence the course of disease progression. This review describes the recently approved DMARD leflunomide, an isoxazole-based immunomodulator. Unlike other DMARDs, leflunomide arrests the growth of activated lymphocytes by inhibiting the enzyme dihydroorotate dehydrogenase, a critical link in the production of uridine monophosphate. Leflunomide is rapidly metabolized to the active major metabolite A77 1726, which is responsible for the drug's pharmacologic activity. Leflunomide has exerted inhibitory activity in animal models of RA. Its clinical efficacy has been demonstrated in a number of controlled trials. In two multinational 52-week studies and two 24-week studies, all leflunomide-treated patients received an initial loading dose of 100 mg for 3 days, followed by 20 mg/d. The effects on the signs and symptoms of RA were evaluated using the American College of Rheumatology (ACR) 20 responder index, tender and swollen joint counts and scores, patients' and physician's global assessments, and pain intensity index. Erosions and joint-space narrowing were assessed by radiography. Compared with placebo, leflunomide significantly improved the signs and symptoms of RA (41%-64% improvement) by ACR 20 responder criteria (P < 0.001). Leflunomide, methotrexate, and sulfasalazine were equally effective in terms of symptom outcomes. In terms of retarding the progression of disease, leflunomide was significantly superior to placebo, with no consistent difference from methotrexate or sulfasalazine. In a trial using a combination of leflunomide and methotrexate therapy, 53% of patients were responders by ACR 20 criteria. Adverse effects in RA patients receiving leflunomide included diarrhea, elevated liver enzymes, alopecia, and rash. Additional adverse events occurring with a frequency >5% included allergic reaction, asthenia, abdominal pain, back pain, and hypertension, among others. Thus leflunomide may be used in selected RA patients (ie, those starting RA therapy for the first time or failing earlier DMARD therapy). However, the product labeling requires monthly monitoring of liver enzymes until stable concentrations are reached. Other labeled warnings include a risk of immunosuppression and an increased risk of fetal death or teratogenic effects in pregnant women. Methotrexate, which is also hepatotoxic, is usually the initial DMARD recommended for use in patients with aggressive RA.
Synthesis of two chimeric peptides composed of tuftsin and thymic humoral factor-gamma 2 (THF-gamma 2) conjugates was accomplished. Our goal was the generation of novel immunomodulators. Initially, we demonstrate an IL-6 inducing activity of the phagocytic cells stimulant, tuftsin, on murine macrophages. This activity was documented only in the presence of antigen, either KLH or lysozyme. The augmentation was dose dependent, with optimal activity at a concentration of 200 and 20 nM, respectively. The chimeric peptides, either H2N-tuftsin-THF-gamma 2-OH or H2N-THF-gamma 2-tuftsin-OH, were also evaluated in the IL-6 system in the presence of the more potent antigen, KLH. The IL-6 inducing effect was maintained, although maximal activity appeared only at a concentration an order of magnitude greater than that of tuftsin. The chimeric peptides were further tested in an assay evaluating enhancement in murine bone marrow myeloid colony formation, a system in which THF-gamma 2, a T cell stimulant, has an established beneficial effect. The compounds were found to be inactive at the 25-200 ng/ml (14-112 nM) concentration range evaluated. Finally, the chimeric peptides were tested in a combined macrophages-T cells assay, i.e. antigen presentation, in which H2N-tuftsin-THF-gamma 2-OH was found to be more active than either parent peptide, thus representing a possible therapeutic agent.
The immunomodulating effect of a new polysaccharide-peptide complex from culture mycelia of Lentinus edodes (LE) was studied for elucidation of the mechanism of augmentation of cell-mediated immunity. RNA samples were isolated from the untreated and treated murine splenocytes and human peripheral blood mononuclear cells. RT-PCR was used to analyze the cytokine gene expression and bioassay was used to analyze the cytokine production. By administration of LE, the expression levels of IL-2 and TNF-alpha genes were augmented in the treated murine spleen mononuclear cells and human peripheral blood mononuclear cells. The production of IL-2 were augmented in the treated murine spleen mononuclear cells, and the production of TNF-alpha were augmented in the treated murine peritoneal exudate macrophages. The production of IL-2 and TNF-alpha were augmented in the treated human peripheral blood mononuclear cells. These results suggest that LE may induce Th immune responses.
Product R (Reticulose(TM)) is a peptide-nucleic acid immunomodulator with broad-spectrum antiviral activity that was recently shown to increase expression of mRNAs encoding the proinflammatory cytokines, IFN-gamma, IL-1beta, IL-6 and TNF-alpha. Since these cytokines induce expression of the chemokines, MIP-1alpha, MIP-1beta, RANTES, and SDF-1, all of which inhibit viral infectivity, we were interested to determine if Product R also alters chemokine expression. In addition, the finding, that Product R decreases HIV-1 RNA and extracellular p24 antigen in H9 T-lymphoma cells, suggested to us that this drug may block viral infection by reducing the expression of chemokine receptors on target cells. We have therefore utilized H9 cells to test the effects of Product R on expression of mRNAs encoding the chemokine receptors, CD4, CXCR4 and CCR5, as well as their ligands, IL-16, SDF-1, MIP-1alpha, MIP-1beta, and RANTES, by RT-PCR. We also assayed the effect of Product R on surface receptor expression by flow cytometry, and on the chemotactic activity of these cells towards the CXCR4 ligand, SDF-1, and the CCR5 ligands, MIP-1alpha and RANTES. H9 cells were cultured for 3-21 days in medium containing 5% or 10% Product R, or 5% or 10% PBS. We found that, compared to control cultures, cells cultured in media containing Product R expressed lower amounts of CXCR4 and CCR5 mRNA and surface antigen at all time points. Culture for 3 days in media containing Product R also reduced the ability of cells to migrate towards 10-20 ng/ml SDF-1 and 100-250 ng/ml RANTES. In contrast, Product R had no effect on the expression of CD4 mRNA and receptor protein, or on expression of IL-16 mRNA. These findings suggest that Product R may have clinical efficacy in HIV-1-infected patients by downregulating viral coreceptors on target T-cells.
A disease gets manifested only when the host immune system is not strong enough to fight off the infective agents. A number of small peptides both from natural and synthetic origin are found to be capable of modulating the immune response. While immune adjuvants are known to strengthen the immune response and help the host not to give way to the pathogens thereby preventing their establishment, the immunosuppressors are found useful in autoimmune conditions as well as in facilitating the organ transplants. Recent understanding of immune network, however, reveals its cross connectivity with the endocrine and central nervous systems as well. Thus, the inhibition and control of disease by planned restoration of homeostatis in these systems through immunomodulation is also possible.
In this study, we examined whether lipopolysaccharide (LPS)-, interferon-gamma (IFN-gamma) or 16,16-dimethyl prostaglandin E2 (dmPGE2)-pretreatment of stimulator spleen cells from C57BL6 (B6) mice affects effector function of responder T-lymphocyte from C3H/HeJ mice. Stimulation of B6-derived splenic mononuclear cells (SMNCs) with LPS (10 micrograms/ml) prior to their utilization as stimulator cells in a mixed lymphocyte culture (MLC) resulted in an increase in responder T-lymphocyte proliferation compared to utilization of unstimulated SMNC (P < 0.05). IFN-gamma demonstrated similar effects in a dose dependent fashion with maximal stimulatory effect seen at 1000 U/ml. In contrast, pretreatment of stimulator SMNC with dmPGE2 resulted in dose-dependent inhibition of the responder T-lymphocyte proliferation with maximum inhibitory effect seen using a concentration of dmPGE2 of 10(-5) M. The presence of indomethacin in the MLC did not reverse this effect. These data demonstrate the effect of immunomodulation of stimulator spleen cells on subsequent T-lymphocyte function.
Linomide (quinoline-3-carboxamide) is an immunomodulator with diverse effects on the immune system. Its beneficial effects on experimental autoimmune disease models have been linked to downregulation of Th1 cytokines and altered macrophage functions. We studied this effect of downregulation of Th1-type of immune response on Semliki Forest A7 virus infection in experimental autoimmune encephalomyelitis (EAE) susceptible Th1-prone SJL mice and in EAE-resistant Th2-prone BALB/c mice. We aimed at addressing the target-cell population of Linomide responsible for this Th1 downregulation. Treatment with Linomide led to increased virus infection in brain and this effect coincided with decreased production of IL-12 and IFN-gamma from stimulated spleen cells in SJL mice. In contrast, IL-12 and IFN-gamma expression were increased in Linomide-treated BALB/c mice. Treatment of infected SJL mice resulted in decreased percentage of CD11b+ and CD11c+ cells. Thus, the target cell population of Linomide may be antigen-presenting cells (APC) which are considered as candidates for regulatory cells of Th1/Th2 balance.
The effects of chemical sympathectomy on moxibustion-induced changes in splenic natural killer (NK) cell cytotoxicity, T and B cell proliferation were studied. Direct moxibustion was applied to the unilateral Zusanli region. NK cell cytotoxicity was suppressed by moxibustion in both vehicle-treated rats and sympathectomized rats. T cell proliferation was not affected by moxibustion. B cell proliferation showed no significant change in vehicle-treated rats, but an increase was seen in sympathectomized rats treated with moxibustion. Sympathectomy alone induced an augmentation of NK cell cytotoxicity and a suppression of T cell proliferation. These results suggest that the sympathetic nervous system (SNS) has no significant role in the mechanism of moxibustion-induced immunomodulation.
Multiple sclerosis (MS) is the most common disabling neurological disease of young adulthood. Following advances in the understanding of the immunological mechanisms that underlie the pathogenesis of MS, a growing arsenal of immunomodulatory agents is available. Two classes of immunomodulators are approved for long-term treatment of MS, the efficacy of several promising new concepts is being tested in clinical trials and classical immunosuppressive agents used in MS treatment have been shown to exert specific, immunomodulatory effects. Furthermore, two recent observations have changed our basic understanding of the pathogenesis of MS. First, immune cells in MS lesions have neuroprotective activity, which indicates a beneficial role of neuroinflammation. Second, there is evidence that axonal loss, rather than demyelination, underlies the progression of MS and, hence, constitutes a therapeutic target.
Individual differences in the exploratory response to novelty were found to be related with the vulnerability to develop stress-induced immunological alterations. We studied the effect of exposure to inescapable shock on antibody formation against sheep red blood cells (SRBC) in rats selected according to their locomotor activity in a novel situation. Interestingly, antibody titers were only enhanced in shocked animals with the highest locomotor activity. These results emphasize the importance of taking into account individual differences for the study of the mechanisms involved in stress-induced immunomodulation, suggesting a behavioral procedure (novelty reactions) to deal with individual variability in the effects of stress on the immune system.
Mannosylated liposomes were prepared by incorporating cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiomannosylethyl)amino)butyl)formamide (Man-C4-Chol) into small unilamellar liposomes consisting of cholesterol and distearoyl phosphatidylcholine (DSPC). The biodistribution of liposomes labeled with [3H]cholesteryl hexadecyl ether was examined in mice. The rate and extent of the hepatic uptake of those [3H]liposomes increased proportionally on increasing the mixing ratio of Man-C4-Chol. Their hepatic uptake was reduced by increasing the administered dose due to the limited number of mannose receptors. The liver uptake of [3H]Man-liposomes was preferentially mediated by liver non-parenchymal cells (NPC) and significantly inhibited by co-injection with an excess of Man-BSA, indicating the involvement of a mannose receptor-mediated mechanism in the hepatic uptake of Man-liposomes. Muramyl dipeptide (MDP), an immunomodulator, was also incorporated into the liposomes and its inhibitory effect in an experimental liver metastasis model was examined. In contrast to free MDP treatment, which showed little effect on the inhibition of metastasis, liposomal MDP significantly reduced the number of metastatic colonies in the liver. Active targeting of MDP to liver NPC by Man-liposomes resulted in more effective inhibition than delivery of MDP by liposomes without mannose. Treatment with MDP/Man-liposomes further increased the survival of the tumor-bearing mice. These results suggest that Man-liposomes are effective carriers for targeted delivery of bioactive compounds to liver NPC.