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Biologics in development for the treatment of moderate to severe plaque-type psoriasis are discussed in this article. Immunomodulators used as therapeutic, pathogenic probes will continue to identify targets that play primary roles in the pathogenesis of psoriasis.
Human isolates of Propionibacterium acnes and Staphylococcus saprophyticus could be shown to liberate low molecular weight peptides (MW less than 6.500 D) with immunomodulating activity. FACS analyses of BALB/c-mouse lymphoid cells from the thymus and spleen revealed an enhanced percentage of T-helper cells after peptide administration. Intestinal microflora decontamination of BALB/c-mice considerably reduced immune cell function and lymphatic tissue proliferation. Apparently, lack of peptide production or liberation correlated to immunosuppression. Substitution of peptides (from P. acnes or S. saprophyticus) to decontaminated mice reconstituted immune cell function and proliferation. Cortisone-resistant thymocytes were used as an experimental equivalent of functional cells in the thymus. Thus, cortisone treatment of BALB/c-mice significantly reduced the number of thymocytes, however, administration of microbial peptides restored the thymus population.
The ability of bacteria and bacterial products to modulate the immune response to unrelated antigens is well documented. Propionibacteria are amongst the most potent immunomodulators stimulating cell populations involved in nonspecific resistance. Generally, the activated immune system provides protection from infectious pathogens and malignancies via mechanisms of recognition and elimination. Accordingly, administration of propionibacteria could be shown to be of benefit in the treatment of neoplastic and infectious diseases. Thus, it can be recommended for further clinical investigations.
A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.
HMG-CoA reductase inhibitors, or statins, are effective lipid lowering agents, extensively used in medical practice. Statins have never been shown to be involved in the immune response, although few clinical reports have suggested a better outcome of cardiac transplantation in patients under pravastatin therapy. Major histocompatibility complex class II (MHC-II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. Whereas only a limited number of specialized cell types express MHC-II constitutively, numerous other cells become MHC-II positive upon induction by interferon gamma (IFN-gamma). We and others recently demonstrated that statins act as direct inhibitors of induction of MHC-II expression by IFN-gamma and thus as repressors of MHC-II-mediated T cell activation. This effect was observed in several cell types, including primary human endothelial cells and macrophages. Interestingly, this inhibition is specific for inducible MHC-II expression and does not concern either constitutive expression of MHC-II or expression of MHC-I. In repressing induction of MHC-II, and subsequent T lymphocyte activation, statins therefore behave as a novel type of immunomodulator. This unexpected effect provides a scientific rationale for suggesting the use of statins as novel immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.
The microbial biotransformation of HR325 [2-cyano-3-cyclopropyl-3-hydroxy-N-(4'-trifluoromethyl-3'-methylphenyl)- propenamide], a synthetic immunomodulating agent, has been investigated in order to be compared with animal metabolism and to prepare some metabolites which are difficult to obtain by chemical methods. Several fungal strains are able to completely metabolize this drug. Mortierella isabellina NRRL 1757 only achieves a benzylic hydroxylation on the aromatic methyl group, affording in high yield the corresponding hydroxymethyl derivative. In addition, other strains, such as Cunninghamella elegans ATCC 26269 or Beauveria bassiana ATCC 7159 can cleave both cyclopropyl and cyano groups in a new unknown oxidative biochemical reaction, which can be mimicked by m-chloroperbenzoate oxidation. The resulting cyanohydrin is hydrolyzed and reduced to a primary alcohol. In B. bassiana, the final incubation product is a beta-4-O-methylglucoside derivative of this alcohol, and has been fully characterized by independent synthesis. The different metabolic patterns of HR325 in the three fungal strains are discussed, and a mechanistic hypothesis about the oxidative cleavage of the right part of the molecule is proposed. The production of microbial metabolites is compared to animal metabolism in terms of structure and efficiency.
Exposure to ultraviolet (UV) radiation, particularly the UVB wavelengths, leads not only to DNA damage but also to suppression of cell-mediated immunity to antigens encountered shortly after the irradiation. One initiator of this complex process is cis-urocanic acid (cis-UCA), which is formed from the naturally occurring trans isomer in the epidermis on absorption of UV. cis-UCA has been shown to have immunomodulating properties in a variety of in vivo and in vitro experimental systems, although its mechanism of action is not yet clear. This article covers methods of preparing cis-UCA and of analyzing UCA isomers in various human and mouse tissues. Experiments that demonstrate that cis-UCA is immunosuppressive are described. The final section deals with the preparation and characterization of a monoclonal antibody with specificity for cis-UCA.
Recently, the intriguing possibility has been raised that heart failure may be mediated by the biological effects of cytokines. Indeed, we found elevation of plasma concentrations of various cytokines in patients with myocardial disease. We also detected positive tumor necrosis factor (TNF-alpha) immunoreactivity in right atrial tissues obtained during surgery from patients with severe heart failure. Therefore, we postulated that some aspects of heart failure may be related to non-lethal down-modulation of cardiac function by immune cells and their cytokines. Testing this hypothesis in an experimental model of murine myocarditis, we found that injection of recombinant human TNF-alpha increased mortality of the animals infected with myocarditis virus. The anti-TNF-alpha monoclonal antibody improved survival and attenuated the myocardial lesions. Whereas, administration of recombinant human IL-2 in the acute viremic stage increased survival rate, and resulted in less intense pathological changes in the myocardium while in the subacute aviremic stage, the same amount of IL-2 reduced survival rate and exacerbated severity of the disease. Therefore, cytokine release may initiate a beneficial inflammatory and immune response in the acute phase of the disease process, but the continued induction of cytokines and the enhanced natural killer (NK) cell activity in the later stage are no longer protective. Vesnarinone, a recently synthesized inotropic agent which has proved to benefit patients with congestive heart failure by improving prognosis, also increased the survival of individual subjects in the above-mentioned murine model of heart failure. Cytotoxicity of NK cells obtained from the virus infected animals was substantially reduced when treated with vesnarinone. Vesnarinone also inhibited production of TNF-alpha and other cytokines from stimulated human lymphocytes and cultured murine splenocytes. We conclude, therefore, that inhibition of NK cell activity and suppression of cytokine production appear to be important immunological defense mechanisms which could contribute to the observed salutary effects of vesnarinone in the treatment of chronic heart failure. More broadly, immunomodulation could pave the way for a new frontier in the management of heart failure.
Long-term display of exogenous proteins on the cell surface may have important research and therapeutic implications. We report a novel method for the cell-surface display of proteins that involves generation of a chimeric protein with core streptavidin, biotinylation of cells, and "decoration" with the protein. A chimeric protein with the extracellular portions of FasL (SA-FasL) was efficiently displayed on the cell surface within 2 hr without detectable cellular toxicity. Biotin and SA-FasL persisted on the cell surface for weeks in vitro and in vivo. Immunomodulation with SA-FasL-decorated splenocytes effectively blocked alloreactive responses in naive and presensitized rodents and prevented the rejection of allogeneic pancreatic islets. This approach may serve as an alternative to gene transfer-based expression with broad research and therapeutic applications.
Our goal is to develop cell vaccines against leukemia cells, genetically modified to express molecules with potent immune-stimulatory capacities. Pre-clinical evaluation of this approach in murine models has demonstrated efficient anti-leukemic responses with the expression of immunomodulators, in particular GM-CSF and CD80, in irradiated cell vaccines. We have previously shown efficient insertion of GM-CSF and CD80 genes into primary human leukemia cells with the use of second and third generation self-inactivating (SIN) lentiviral vectors (Blood 96 (2000), 1317; Leukemia 16 (2002), 1645). The advantages of lentiviral vectors for development of autologous leukemia cell vaccines include: (1) efficient and consistent gene delivery; (2) high levels of transgene expression; (3) persistent expression of the transduced gene; (4) no viral proteins, as only the transduced gene is expressed; (5) no undesirable cytotoxic effects, and; (6) simplicity of use [leukemia cells are exposed to vector(s) only once]. In this work, we evaluated the insertion of the central polypurine tract and the central termination sequence into a SIN lentiviral vector encoding for GM-CSF and CD80, which significantly enhanced the transduction efficiency of primary leukemia cells and provided higher levels of GM-CSF and CD80 co-expression. We also demonstrate a methodology to deliver simultaneously a combination of immunomodulatory molecules (GM-CSF, CD80, IL-4, and CD40L) to activate different pathways of immune stimulation. Therefore, lentiviral vectors offer a simple, versatile, and reliable approach for engineering leukemic cells for use as cell vaccines.
alpha(1)-Acid glycoprotein (AGP) is a protein with a molecular weight of 41-43 kDa and is heavily glycosylated (45%). Due to the presence of sialic acids, it is negatively charged (pI=2.7-3.2). AGP is an acute phase protein in all mammals investigated to date. The serum concentration of AGP rises several fold during an acute phase response, the systemic answer to a local inflammatory stimulus. Also, its glycosylation pattern can change depending on the type of inflammation. The biological function of this protein is not clear. A number of activities on different type of blood cells have been described. In vivo, AGP clearly has protective effects in several models of inflammation. Here we review the data supporting an anti-inflammatory and immunomodulating role of AGP.
Recombinant antibodies expressed ectopically in plant cells recognize their corresponding antigens and can therefore bind specifically to phytohormones and proteins in vivo. The generation of antibody-antigen complexes interferes with the functions of the targets and affects the phenotype of transgenic plants. Recombinant antibodies can accumulate in different cell compartments and organs of transgenic plants at different stages of development. High levels of expression of specific, high-affinity antibodies are required for immunomodulation. Here, we discuss several models and examples of the antibody-mediated modulation of phytohormone and protein functions in terms of their potential for plant research.
In the past year, important advances have been made in the area of host-related immunomodulatory genes encoded by the larger DNA viruses, particularly for the poxviruses and herpesviruses. Not only has the repertoire of viral immunomodulator homologs expanded as a result of sequencing the complete genome of another six, large DNA viruses, but also new concepts of how they work have been proposed and in some cases supported by in vivo evidence. Recent developments have been made in understanding a spectrum of host-related viral modulators, including complement control proteins, TNF-receptor homologs, IL-18 binding proteins, viral interleukins (vIL-6 and vIL-10), chemokine mimics and chemokine receptor homologs.
Chronic lymphocytic leukaemia (CLL) is a malignant haematological disorder that remains mostly incurable; more than 95% of patients have disease of B-cell origin. Advances with targeted agents such as monoclonal antibodies, antisense therapy, or both these techniques combined with traditional chemotherapy have improved the frequency of remission. The clinical course of CLL is marked by frequent relapse, and there are limited therapeutic options for patients with relapsed or refractory disease. The morphologically mature CLL clone regulates the microenvironment through modulation of the cytokine milieu that aids its growth and survival, and has a role in immune escape. Targeting of the tumour-cell microenvironment has not been investigated as a treatment option for CLL. Immunomodulating agents are a new class of drugs that change expression of various cytokines and that costimulate immune effector cells.
Immunomodulators include both immunostimulatory and immunosuppressive agents. Only recently have the basic mechanisms of topical immunotherapy been elucidated. Besides topical contact sensitisers (eg, diphencyprone or dinitrochlorobenzene), newer agents of the imidazoquinoline family such as imiquimod and resiquimod act by inducing cytokine secretion from monocytes or macrophages (interferon-alpha, interleukin-12, tumour-necrosis factor-alpha). The locally generated immune milieu leads to a Th1-dominance and cell-mediated immunity that have been used clinically to treat viral infections such as human papillomavirus (HPV), herpes simplex virus (HSV), mollusca, and cancerous lesions including initial squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. While these agents improve antigen-presentation by dendritic cells, they also act on B cells and lead to the synthesis of antibodies such as IgG2a much like the recently discovered immunostimulatory CpG-sequences that stimulate innate immunity. These sequences act as "danger signals" since they occur in bacterial and viral DNA, but are selectively methylated and inactivated in the mammalian genome. They share the induction of the same cytokines as imidazoquinolines but they show different magnitudes and kinetics of response. Topical immunotherapy with immunostimulatory agents shows potential for effective and patient-friendly treatment of inflammatory, infectious, and cancerous skin diseases. Immunoenhancers such as imdazoquinolines and CpG-sequences also have adjuvant properties that could improve conventional (protein) and DNA vaccination against cancer, atopy, and allergies.
The effect of morphine administration on immune parameters is well documented. However, there exists a limited knowledge of the effect of morphine's metabolites on immune status. The present study examines the immunomodulatory effects of the morphine metabolite, morphine-6 beta-glucuronide (M6G), in the rat and provides further evaluation of the antinociceptive effects of M6G. Animals were administered phosphate-buffered saline (PBS) or M6G in doses of 1.0, 3.16, or 10.0 mg/kg (subcutaneous (s.c.)) or 0.1, 0.316, or 1.0 microgram (intracerebroventricular (i.c.v.)). Animals were tested for antinociception in the warm water tail-withdrawal procedure. In a separate set of animals, assessments of splenic natural killer cell activity, lymphocyte proliferative responses to mitogenic stimulation, and production of interferon-gamma were made 1 h following the s.c. or i.c.v. administration of M6G. The results show that M6G induced potent antinociception that was evident for at least 120 min following administration. M6G also produced decreases in natural killer cell activity, lymphocyte proliferation, and interferon-gamma production 1 h following both routes of administration. The difference in potency between immune alterations induced by subcutaneous vs. intracerebroventricular administration suggest central mediation of the immunomodulatory properties of M6G. Thus, M6G produces significant antinociception and immunomodulation in the rat. These findings demonstrate potent immunomodulatory properties of a metabolite of morphine, 1M6G.
Occupational or environmental exposure to metals is believed to affect human health adversely. One mechanism whereby metals can alter health is through modulation of immune homeostasis. Imbalances in immune regulation by metals can lead to inadequate or excessive production of inflammatory cytokines. Alternatively, metals can lead to inappropriate activation of lymphoid subsets involved in acquired immunity to specific antigens. Some resultant pathologies may include chronic inflammatory processes and autoimmune diseases. Metals may change the response repertoire by direct and indirect means by influencing expression of new antigens, new peptides, and/or antigen presentation by modifying the antigen-presenting complex. The differences in metal-induced immune responses between humans and the mechanisms of metal immunomodulation are discussed.
In recent years, it has become clear that the immune system has a major role in atherosclerosis development and progression. More specifically, atherosclerosis fulfills all four criteria to define a condition as being an autoimmune in nature. This association also suggests that modification of the immune response in atherosclerosis could affect this process. In this review, we summarize different aspects of immunomodulation in atherosclerosis. These include immunosuppression, active immunization, induction of tolerance, administration of intravenous immunoglobulin, gene therapy, cytokine network manipulation and statins.