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PubMed2006

Immune modulation and reconstitution of HIV-1-specific responses: novel approaches and strategies.

Efficacious protection for future generations from HIV-1 infection through the development of prophylactic vaccines is the best hope for the millions of individuals living with the threat of HIV-1 infection. Advances in the development of non-curative chemotherapy for those already infected have changed the course of the epidemic for those with access to the drugs. However in the ten years since the advent of highly active anti-retroviral therapy, the expectancy of curative chemotherapy has been quashed, and the constant need for a next generation of drugs is evident. As our understanding of HIV-1 pathogenesis increases, it is becoming apparent that novel approaches and strategies will be required to halt the global progression of HIV-1. Immune-based therapies are being considered in the context of effective antiretroviral therapy. Such immune-based therapy must allow the induction or regeneration of HIV-1-specific T-cell responses with the potential to control viremia and purge viral reservoirs. Studies of therapy substitution, treatment interruption, therapeutic vaccines and/or cytokines and/or hormones have been carried out and are briefly summarised in this review.

AIDS Vaccines↗

PubMed2004

Synthesis of immune modulators by smooth muscles.

The primary function of smooth muscle cells is to contract and alter the stiffness or diameter of hollow organs such as blood vessels, the airways and the gastrointestinal and urogenital tracts. In addition to purely structural functions, smooth muscle cells may play important metabolic roles, particularly in various inflammatory responses. In cell culture, these cells have been shown to be metabolically dynamic, synthesizing and secreting extracellular matrix proteins, glycosaminoglycans and a wide variety of cell-cell signaling proteins, such as interleukins, chemokines and peptide growth factors. Secreted cell signaling proteins participate in the inflammatory response of smooth muscle-containing organs, and some can also stimulate smooth muscle migration, proliferation and contraction. The cellular signaling pathways controlling synthesis of these signaling proteins are similar to those used by cells mediating innate immunity and may contribute to pathogenesis of diverse diseases including atherosclerosis, asthma, inflammatory bowel diseases and preterm labor. Appreciating the role of smooth muscle cells in these diseases may lead to better understanding of the beneficial effects of anti-inflammatory drugs as well as identification of new targets for anti-inflammatory therapy.

Animals↗

PubMed1988

Histamine type-2 receptor antagonist immune modulation. I. Increased cell-mediated cytotoxicity in normal and in down-regulated systems.

Cimetidine, a histamine type-2 receptor antagonist, is capable of immunoregulating T cell-mediated proliferative responses in both man and mouse. We present data that show that cell-mediated cytotoxicity (CMC) is also increased by cimetidine in normal and down-regulated murine splenocytes. Timed addition and removal of cimetidine from CMC generation cultures localizes the cimetidine effect to the first 24 hours of the alloantigen sensitization process. Cimetidine partially reverses CMC suppression by suppressor cells generated in vitro in a dose response manner; the result depends on the number of suppressor cells added. Mixed tumor lymphocyte cytotoxicity of splenocytes from syngeneic-tumor-bearing mice is increased by in vivo cimetidine treatment, which results in prolongation of concomitant tumor immunity. These data support the concept that cimetidine may have potential as a clinical immunofacilitator in down-regulated states of immunity.

Animals↗

PubMed2002

Virotherapy clinical trials for regional disease: in situ immune modulation using recombinant poxvirus vectors.

The ability of viruses to readily infect tumor cells both in vitro and in vivo has resulted in their study as antitumor agents through a variety of strategies. Replicating and conditionally replicating viruses and recombinant viruses encoding genes for toxins and/or prodrugs have been studied for their direct antitumor activity with promising results. However, to date, the lack of a targettable construct able to localize to all tumors following systemic administration has proven to be a major limitation in their use for metastatic disease. The ability of a variety of well-characterized viruses to serve as vectors for expression of tumor antigens and/or cytokines has also resulted in their study as immunotherapeutic agents. In this review, we discuss preclinical and clinical data that support the use of recombinant poxviruses as vectors for in situ tumor transfection with immune-enhancing cytokines and immune costimulatory antigens. We hypothesize that such an approach will ultimately lead to enhanced immune recognition of tumor and the development of an effective systemic antitumor immune response capable of eradicating primary and metastatic tumor foci.

Clinical Trials as Topic↗

PubMed2006

Kaposi's sarcoma-associated herpesvirus immune modulation: an overview.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the most recently discovered human herpesvirus. It is the aetiological agent of Kaposi's sarcoma (KS), a tumour frequently affecting AIDS patients not receiving treatment. KSHV is also a likely cause of two lymphoproliferative diseases: multicentric Castleman's disease and primary effusion lymphoma. The study of KSHV offers exciting challenges for understanding the mechanisms of virus pathogenesis, including those involved in establishing infection and dissemination in the host. To facilitate these processes, approximately one-quarter of KSHV genes encode cellular homologues or unique proteins that have immunomodulatory roles in cytokine production, apoptosis, cell signalling and the immunological synapse. The activities of these molecules are considered in the present review and the positions of their genes are mapped from a complete KSHV genome sequence derived from a KS biopsy. The understanding gained enables the significance of different components of the immune response in protection against KSHV infection to be evaluated. It also helps to unravel the complexities of cellular and immunological pathways and offers the potential for exploiting viral immunomodulators and derivatives in disease therapy.

Apoptosis↗

PubMed2001

Delayed-type hypersensitivity and humoral immunity modulation by dietary lipids in a murine model of pulmonary tumorigenesis induced by urethan.

Mice fed on semisynthetic formulas containing 15% of corn oil (CO), cod fish liver oil (FO), oleic acid (O) or a mixture of 46% of palmitic and 50% of stearic acids (PS) were treated with urethan during 18 weeks for lung tumor induction. Delayed-type hypersensitivity (DTH) assay, hemagglutination assay and the amount of lung nodes (alveolar adenocarcinomas) were recorded. Results showed significantly greater DTH in CO and FO with respect to O and PS feeding mice; the two last ones induced an essential fatty acid (EFA) deficiency (EFAD). In the O lot there was a non-significant diminution of the humoral response. EFAD animals exhibited a tendency to increase number of lung nodes in relation to CO and FO lots. Splenomegalia was recorded in FO lot. Confront between spleen weight and DTH showed a 72% correlation, suggesting an increase in cellular immunity as increasing unsaturation. It may be concluded that in this suitable model of tumorigenesis the manipulation of dietary lipids may be a strategy to modify the immune system response.

Adenocarcinoma↗

PubMed2025

CCT8 drives colorectal cancer progression via the RPL4-MDM2-p53 axis and immune modulation.

PURPOSE: Colorectal cancer (CRC) ranks high in global mortality, emphasizing the need for effective interventions. The aim of the research is to elucidate the oncogenic role of CCT8 in CRC and its interaction with RPL4 in the RPL4-MDM2-p53 axis. METHODS: TIMER 2.0, TCGA, and GTEx databases were used to analyze CCT8 expression patterns in CRC. Immunohistochemistry was performed to examine CCT8 distribution in CRC tissues and adjacent non-tumor tissues. Functional assays, including CCK-8, transwell, wound-healing, and flow cytometry, were conducted using DLD-1 and HCT116 cell lines to assess the effects of CCT8 on cell proliferation, migration, invasion, and apoptosis. Gene set enrichment analysis, protein-protein interaction network analysis, and co-immunoprecipitation were performed to explore the interaction between CCT8 and RPL4 and their role in the RPL4-MDM2-p53 pathway. Additionally, gene set variation analysis was applied to investigate the relationship between CCT8/RPL4 expression and immune infiltration patterns in CRC. RESULTS: CCT8 was significantly upregulated in CRC and associated with tumor progression. Mechanistically, CCT8 potentially synergizes with RPL4 concluded from their positive correlation and similar immune infiltration patterns, influencing the RPL4-MDM2-p53 axis and contributing to p53 ubiquitination and degradation. CONCLUSION: These findings underscore the oncogenic significance of CCT8 in CRC and shed light on its molecular mechanisms, paving the way for potential therapeutic applications.

Humans↗

PubMed2006

Influenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients.

OBJECTIVES: To compare serological response to influenza vaccine in patients with long-standing rheumatoid arthritis (RA) treated with tumour necrosis factor (TNF) blockers and/or methotrexate (MTX) and controls. METHODS: Altogether, 149 patients with RA and 18 healthy subjects were vaccinated. Fifty patients were treated with TNF blockers (etanercept or infliximab) in combination with MTX (TNF blockers + MTX), while 62 patients received TNF blockers alone or with other disease-modifying anti-rheumatic drugs (DMARDs) (TNF blockers without MTX). Thirty-seven patients were treated with MTX without TNF blockers (MTX). Vaccination was performed with trivalent vaccine (Influvax or Vaxigrip) both containing 15 microg haemagglutination inhibition (HI) of each of two A strains (H1N1 and H3N2) and one of B strains (B1 or B2). Serum samples were collected prior to and 4-6 weeks after vaccination and titrated against all four strains using HI assay. A positive immune response was defined as > or =4-fold increase compared with pre-vaccination titre levels. A titre > or =40 was considered protective. Pre- and post-vaccination geometric mean titres (GMT) were compared. RESULTS: Post-vaccination titre levels increased significantly in all groups, also reflected by high frequencies of positive immune responders. A positive immune response to combinations of all strains was significantly better for the MTX group. Individuals with protective levels before vaccination responded less well as a group. CONCLUSIONS: RA patients treated with MTX without TNF blockers had significantly better serological response to influenza vaccination compared with those receiving TNF blockers alone or in combination with MTX and/or other DMARDs. However, the immune response is sufficiently large to warrant influenza vaccination to all RA patients regardless of treatment.

Antibodies, Monoclonal↗

PubMed2001

The role of phytosterols and phytosterolins in immune modulation: a review of the past 10 years.

Although plant sterols (phytosterols) were chemically described in 1922, their biological role in human and animal health has been underestimated. Their ability to control cholesterol plasma levels in hypercholesterolimic patients was first described in 1983 when the structure of phytosterols implied that they could, by steric hindrance, inhibit the absorption of cholesterol from our diets. This has led to the development of functional foods containing high contents of these plant molecules or their esters as cholesterol controlling foods. Over the last 15 years, however, several reports have appeared in the literature indicating that phytosterols have some immunological activity as highlighted in animal models of inflammation or even in in-vitro and in-vivo models of cancer (colorectal and breast cancer). These findings were paralleled by epidemiological studies correlating the reduced risk of numerous diseases and the dietary intake of phytosterols. It is only in the last 10 years, however, that their direct immune modulatory activity on human lymphocytes has been proven and the mechanism of action in cancer cells has been elucidated. The use of phytosterols as supportive therapies in certain chronic conditions has been tested under clinical trial conditions. This review presents a summary of the in-vitro and in-vivo studies published to date.

Adjuvants, Immunologic↗

PubMed2002

Persistent Ross River virus infection of murine macrophages: an in vitro model for the study of viral relapse and immune modulation during long-term infection.

A clinical feature of Ross River virus disease (RRVD) is the periodic relapse of symptoms months after the initial onset of disease. The underlying mechanisms responsible for this relapse have not been determined. In a long-term (148 days) in vitro study of persistently infected murine macrophages we established that RRV infection periodically fell to undetectable biological levels that required genetic detection. However, the virus concentration spontaneously relapsed to biologically detectable levels that corresponded with enhanced viral mRNA expression, cellular detachment, and cytopathic effect. By altering the cell culture conditions we found that relapse could also be induced. We propose that the periodic relapse of symptoms in RRVD may be associated with spontaneous or stress-induced increases in RRV within persistently infected macrophages. This study also established that RRV enhanced macrophage phagocytic activity and dysregulated the immunoregulatory molecules CD80, IFN-gamma, and TNF-alpha that may facilitate persistence of RRV and avoidance of immune responses.

Animals↗

PubMed2002

Inotropic agents and immune modulation.

Since depression of myocardial contractility forms the basis for the development of heart failure, many attempts have been made to enhance the inotropic state of the failing heart by cardiotonic agent as the therapeutic modality. However, large scale clinical trials conducted in the Western societies revealed excess mortality in patients with heart failure received long-term treatment with inotropic agent. Therefore, all of these agents are now regarded as unsuitable for chronic heart failure treatment. In contrast, some inotropic agents with phosphodiesterase inhibitory properties exhibited potential benefits in Japanese patients. In Japan mortality due to heart disease is substantially lower than that found in all other Western countries. Thereby, chronic treatment with inotropic agent may be justified as the optimal care in the context of relief of symptoms and an improved quality of life. The salutary effects of these phosphodiesterase inhibitors appear to be related to anticytokine and immunomodulating effects as well as their cardiotonic action. These findings support the recent new concept that immune responses mediated by cytokines play an important role in the pathogenesis of heart failure.

Adjuvants, Immunologic↗

PubMed2006

Nonsteroid immune modulators and bone disease.

Glucocorticoids have been the main agents for preventing organ rejection,but unfortunately they possess serious side effects. Newer immunosuppressive agents have therefore been introduced to overcome these effects and have had a dramatic impact on reducing the incidence of organ rejection, enhancing donor organ acceptance, and hence patient survival posttransplantation. However, calcineurin inhibitors (CIs), such as cyclosporine and tacrolimus, also have serious effects causing rapid and severe bone loss in animal models and humans. The mechanism accounting for this action is unclear at present, but the role of T lymphocyte action via RANKL seems to be of essence in triggering bone loss. The mechanism is complex and in vitro studies often produce results that are opposite to those seen in vivo. In addition to acute, rapid, and severe bone loss (ARSBL), the clinical picture shows an extremely high incidence of fractures at all sites, and depends upon the organ transplanted, preexisting bone disease, interval before transplantation, and the dose and duration of multiple immunosuppressive drugs. Other immune-modifying drugs, such as azathioprine, mycophenolate mofetil, and sirolimus, which are used in conjunction with glucocorticoids and CIs have not been shown to promote bone loss experimentally or clinically. With the exception of glucocorticoids, all of the agents discussed here demand further investigation with regard to their effects on bone health in the clinical setting.

Bone Diseases↗

PubMed2003

Transfected Plasmodium knowlesi produces bioactive host gamma interferon: a new perspective for modulating immune responses to malaria parasites.

Transgenic pathogenic microorganisms expressing host cytokines such as gamma interferon (IFN-gamma) have been shown to manipulate host-pathogen interaction, leading to immunomodulation and enhanced protection. Expression of host cytokines in malaria parasites offers the opportunity to investigate the potential of an immunomodulatory approach by generating immunopotentiated parasites. Using the primate malaria parasite Plasmodium knowlesi, we explored the conditions for expressing host cytokines in malaria parasites. P. knowlesi parasites transfected with DNA constructs for expressing rhesus monkey (Macaca mulatta) IFN-gamma under the control of the heterologous P. berghei apical membrane antigen 1 promoter, produced bioactive IFN-gamma in a developmentally regulated manner. IFN-gamma expression had no marked effect on in vitro parasite development. Bioactivity of the parasite-produced IFN-gamma was shown through inhibition of virus cytopathic effect and confirmed by using M. mulatta peripheral blood cells in vitro. These data indicate for the first time that it is feasible to generate malaria parasites expressing bioactive host immunomodulatory cytokines. Furthermore, cytokine-expressing malaria parasites offer the opportunity to analyze cytokine-mediated modulation of malaria during the blood and liver stages of the infection.

Animals↗

PubMed2006

A rat model for acute rise in intraocular pressure: immune modulation as a therapeutic strategy.

PURPOSE: To establish a rat model of acute increase in intraocular pressure (IOP) and to investigate the therapeutic window for protection against death of retinal ganglion cells (RGCs) by vaccination with glatiramer acetate (Cop-1) or by treatment with brimonidine or MK-801. DESIGN: Animal study, laboratory investigation. METHODS: IOP was transiently increased in anesthetized Lewis rats by infusing normal saline (0.9%) into the anterior chamber of the eye for one hour. RGC survival was assessed one week and two weeks later by counting the RGCs retrogradely labeled with rhodamine dextran. MAIN OUTCOME MEASURES: RGC survival. RESULTS: IOP rose to 100 cm H(2)O (76 mm Hg) and returned to baseline after 24 hours. The RGC count decreased by 23% a week after the insult and by a further 7% after the second week. Vaccination with Cop-1 on the day of the insult prevented 50% of the IOP-induced RGC loss. Similar neuroprotection was achieved by daily intraperitoneal injections of brimonidine, but not with MK-801. CONCLUSIONS: A transient increase in IOP to 100 cm H(2)O causes death of RGCs in rats. A single immunization with Cop-1 or daily injections of brimonidine protected up to 50% of potentially doomed RGCs from IOP-induced death, suggesting that not all of the cell death in the untreated model results from the IOP insult directly, but that some of it is caused by insult-induced environmental cytotoxicity, which is unrelated to glutamate toxicity or at least to NMDA receptors. These findings can be applied immediately as a basis for acute glaucoma therapy.

Acute Disease↗

PubMed2026

PTBP1 at the host-virus interface: mechanistic roles in viral RNA translation, replication, and immune modulation.

Viruses require the involvement of host RNA binding proteins for completion of important steps of their life cycle. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA-binding protein found ubiquitously which performs important regulatory functions like alternative splicing, RNA stability, RNA localization, and translation by virtue of its four RRMs and shuttling between nucleus and cytoplasm. There is increasing evidence showing that many viruses make use of such regulatory roles of PTBP1 to facilitate their gene expression and replication. This review describes the existing mechanistic knowledge about the PTBP1 functions during viral infection, paying attention to the role of PTBP1 in viral RNA translation, viral RNA genome replication, and regulation of host antiviral response. Special attention is paid to the regulation by PTBP1 of IRES-dependent translation of enteroviruses and hepatitis C virus, as well as to the PTBP1 contribution to RNA stabilization, long-distance RNA interactions, and genome cyclization of flaviviruses such as dengue virus and Japanese encephalitis virus. Recent data on the PTBP1 function in coronavirus RNA metabolism are discussed as well. Furthermore, the role of PTBP1 in being both proviral and antiviral is reviewed in terms of innate immunity signalling pathways, stress granule biology, and virus-host interaction. Finally, we will explore the possibility of PTBP1 being used as a host-directed antiviral drug target despite the hurdles in doing so considering its multifunctionality as an essential cellular RNA-binding protein.

Polypyrimidine Tract-Binding Protein↗

PubMed2005

The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity.

FTY720 is a novel immunomodulatory agent that inhibits lymphocyte trafficking and prevents allograft rejection. FTY720 is phosphorylated in vivo, and the phosphorylated drug acts as agonist for a family of G protein-coupled receptors that recognize sphingosine 1-phosphate. Evidence suggests that FTY720-phosphate-induced activation of S1P1 is responsible for its mechanism of action. FTY720 was rationally designed by modification of myriocin, a naturally occurring sphingoid base analog that causes immunosuppression by interrupting sphingolipid metabolism. In this study, we examined interactions between FTY720, FTY720-phosphate, and sphingosine-1-phosphate lyase, the enzyme responsible for irreversible sphingosine 1-phosphate degradation. FTY720-phosphate was stable in the presence of active sphingosine-1-phosphate lyase, demonstrating that the lyase does not contribute to FTY720 catabolism. Conversely, FTY720 inhibited sphingosine-1-phosphate lyase activity in vitro. Treatment of mice with FTY720 inhibited tissue sphingosine-1-phosphate lyase activity within 12 h, whereas lyase gene and protein expression were not significantly affected. Tissue sphingosine 1-phosphate levels remained stable or increased throughout treatment. These studies raise the possibility that disruption of sphingosine 1-phosphate metabolism may account for some effects of FTY720 on immune function and that sphingosine-1-phosphate lyase may be a potential target for immunomodulatory therapy.

Aldehyde-Lyases↗

PubMedDate not supplied

Induction of donor-specific immune modulation and successful renal transplantation with a simplified method of donor-specific blood transfusion.

We developed a new method of donor-specific blood transfusion (DST) for prospective kidney transplant recipients from a living related donor. Forty-four patients were transfused with 100 ml of one-haplotype matched kidney donor's whole blood at 1, 8, and 15 days after its storage. Ten of these patients received azathioprine (1.5 mg/kg per day) in addition to DST. After DST, three patients (6.8%) developed donor-specific lymphocytotoxic antibodies. The incidence of sensitization was not different between azathioprine-treated and untreated patients. Following DST, donor-specific mixed lymphocyte culture (MLC) was significantly suppressed without any accelerated (secondary type) response in early MLC. Subsequently, 24 patients received a kidney transplant from the donor. Graft survival rates were 96% and 90% at 12 and 24 months, respectively. Nine additional patients, seven from a two-haplotype matched sibling and two from a no-haplotype matched sibling also received DST. None of these patients became sensitized following DST, and all have functioning grafts for 6 to 18 months. This study indicates that 100 ml of stored whole blood DST three times at weekly intervals is a practical, less immunizing, and effective approach to enhance graft survival in recipients of a living related donor graft, DST produces donor-specific adaptive responses that might be conductive to successful graft outcome, and this protocol could be used in sibling donor-recipient pairs who do not share a haplotype.

Adult↗

PubMed2006

Associations of classic Kaposi sarcoma with common variants in genes that modulate host immunity.

Classic Kaposi sarcoma (CKS) is an inflammatory-mediated neoplasm primarily caused by Kaposi sarcoma-associated herpesvirus (KSHV). Kaposi sarcoma lesions are characterized, in part, by the presence of proinflammatory cytokines and growth factors thought to regulate KSHV replication and CKS pathogenesis. Using genomic DNA extracted from 133 CKS cases and 172 KSHV-latent nuclear antigen-positive, population-based controls in Italy without HIV infection, we examined the risk of CKS associated with 28 common genetic variants in 14 immune-modulating genes. Haplotypes were estimated for IL1A, IL1B, IL4, IL8, IL8RB, IL10, IL12A, IL13, and TNF. Compared with controls, CKS risk was decreased with 1235T/-1010G-containing diplotypes of IL8RB (odds ratio, 0.49; 95% confidence interval, 0.30-0.78; P = 0.003), whereas risk was increased with diplotypes of IL13 containing the promoter region variant 98A (rs20541, alias +130; odds ratio, 1.88; 95% confidence interval, 1.15-3.08; P = 0.01) when considered in multivariate analysis. Risk estimates did not substantially vary by age, sex, incident disease, or disease burden. Our data provide preliminary evidence for variants in immune-modulating genes that could influence the risk of CKS. Among KSHV-seropositive Italians, CKS risk was associated with diplotypes of IL8RB and IL13, supporting laboratory evidence of immune-mediated pathogenesis.

Adult↗