Immune modulation by ultraviolet light.
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Animals↗
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Consequences and implications to FDA regulations of immune modulation by chemicals.
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Animals↗
Antitumor therapy based on the use of an immune modulator, arginine butyrate and interferon.
The analysis of the likely physiological role of interferon during pregnancy and antitumor protection can be employed in developing a new strategy in antitumor therapy. Indeed, pretreatment of the patients with a potent immune stimulation compensates to some extent interferon's immune repressive effects. Through the modulation of the cytoskeleton, interferon enhances macrophage activity. Moreover, butyrate by its own effect on the malignant phenotype increases interferon sensitivity in a number of malignant cells. All of these substances should be used at the lowest possible concentration delivered as closely as possible to the target area.
Amniotic Fluid↗
Chronic exposure to a trichloroethylene metabolite in autoimmune-prone MRL+/+ mice promotes immune modulation and alopecia.
The industrial solvent trichloroethylene (TCE) is a widespread environmental contaminant known to impact the immune system. In the present study, female MRL+/+ mice were treated for 40 weeks with trichloroacetaldehyde hydrate (TCAH), a metabolite of TCE, in the drinking water. The results were compared with the data from an earlier study in which MRL+/+ mice were exposed to TCAH for 4 weeks. Following a 40-week exposure, the mice developed skin inflammation and dose-dependent alopecia. In addition, TCAH appeared to modulate the CD4(+) T-cell subset by promoting the expression of an activated/effector (i.e., CD62L(lo)) phenotype with an increased capacity to secrete the proinflammatory cytokine interferon-gamma. However, unlike what was observed after only 4 weeks of exposure, TCAH did not significantly attenuate activation-induced cell death (AICD) or the expression of the death receptor FasL in CD4(+) T cells. Some metalloproteinases (MMPs) are thought to play a role in susceptibility to AICD by inducing FasL shedding. Thus, both the 4- and 40-week sera were tested for MMP-7 levels in an attempt to explain the disparate results of TCAH on AICD and FasL expression. Serum MMP-7 levels were significantly higher in mice exposed to TCAH for 4 weeks. In contrast, the serum MMP-7 levels were increased in all the mice by 40 weeks when compared with a nonautoimmune strain. Taken together, a chronic exposure to TCAH promotes alopecia and skin inflammation. The early effects of TCAH on MMP-7 levels may provide a mechanism by which TCAH promotes skin pathology.
Administration, Oral↗
Humoral immune response to the capsid components of recombinant adenoviruses: routes of immunization modulate virus-induced Ig subclass shifts.
This study examines in detail the capsid-specific humoral immune response of BALB/c mice after one single injection of a replication-defective adenovirus. Two routes of immunization, intravenous (i.v.) and intraperitoneal (i.p.), were compared for the response induced against the adenovirus particle and the three major components of the viral capsid, hexon, penton base, and fiber. A single immunization with the replication-defective adenovirus induces a long and persistent humoral response specific for the virus. However, the molecular components of the viral capsid are differentially recognized depending on the route of immunization. The sera from mice immunized i.p. recognized only the hexon protein and a preferential switch to the IgG2a subclass was obtained which remained stable 100 days post-immunization. The sera obtained from mice immunized i.v. gave a more complex response. At the beginning of the response, an isotype bias toward the IgG2a subclass was observed, but the isotype distribution changed during the whole period of the response. Neutralizing activity was maximum 45 days after immunization by both routes, and no activity was detectable after 3 months. However, the i.v. serum displayed a higher neutralizing activity than the i.p. serum. The IgM antiviral antibodies appeared to be an important component of the neutralizing activity, and the two routes of immunization do not induce the same IgG isotypes to neutralize viral infectivity. Extension of these findings to human gene therapy using recombinant adenoviruses may help to characterize the precise viral protein targets of neutralizing antibodies.
Adenoviruses, Human↗
Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox.
Macrophages, T cells, and B cells of the immune system are central targets of deoxynivalenol (DON) and other trichothecenes-mycotoxins that can be immunostimulatory or immunosuppressive depending on dose, exposure frequency and timing of functional immune assay. Notably, low dose trichothecene exposure transcriptionally and post-transcriptionally upregulates expression of cytokines, chemokines and inflammatory genes with concurrent immune stimulation, whereas high dose exposure promotes leukocyte apoptosis with concomitant immune suppression. DON and other trichothecenes, via a mechanism known as the ribotoxic stress response, bind to ribosomes and rapidly activate mitogen-activated protein kinases (MAPKs). The latter are important transducers of downstream signaling events related to immune response and apoptosis. Using cloned macrophages, our laboratory has identified two critical upstream transducers of DON-induced MAPK activation. One transducer is double-stranded RNA-(dsRNA)-activated protein kinase (PKR), a widely-expressed serine/theonine protein kinase that can be activated by dsRNA, interferon, and other agents. The second transducer is hematopoetic cell kinase (Hck), a non-receptor associated Src family kinase. Inhibitors and gene silencing studies have revealed that Hck and PKR play roles in DON induced gene expression and apoptosis. Future studies should focus on the molecular linkages between these kinases and trichothecene toxicity.
Adjuvants, Immunologic↗
Immune modulation with high-dose heat-shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis.
Immunization with heat-shock protein (HSP) gp96 elicits protective immunity to the cancer or virus-infected cells from which it is derived. Low doses of gp96 generate immunity, while doses 10 times the immunizing dose do not. We show here that injection of high doses of gp96 generates CD4(+) T cells that down-regulate a variety of ongoing immune responses. Immunization with high doses of gp96 prevents myelin basic protein- or proteolipid protein-induced autoimmune encephalomyelitis in SJL mice and the onset of diabetes in non-obese diabetic mice. The suppression of immune response can be adoptively transferred with CD4(+) cells and does not partition with the CD25 phenotype. The immunomodulatory properties of gp96 (and possibly other HSP) may be used for antigen-specific activation or suppression of cellular immune responses. The latter may form the basis for novel immunotherapies for autoimmune diseases.
Adoptive Transfer↗
The dualistic nature of immune modulation in Alzheimer's disease: lessons from the transgenic models.
There is extensive evidence that changes in immune system activation accompany the pathological changes of Alzheimer's disease (AD), but a mechanistic understanding of how the immune system actually participates in disease pathogenesis is still largely lacking. Because of the complexity of the immunological response, and the difficulty in identifying the key molecular players that underlie any given immunological response, expanding our understanding of the immunological response in AD beyond its descriptive stages has not been a straightforward exercise. The development of transgenic animals that form deposits of Abeta peptide in their brains has provided an unexpected dividend to those interested in the immunological response characterizing AD. Several of these transgenic models develop structures greatly resembling neuritic plaques, a hallmark feature of AD brain that is also a focal point of the immunological response occurring in AD. Genetic and pharmacological manipulation of these Abeta-depositing transgenic mice is providing some intriguing and unexpected insights into the role of innate and adaptive immune mechanisms in the pathogenesis of AD. This review will discuss immunological perspectives that have arisen from research using Abeta-depositing transgenic mice, and place these perspectives in the context of epidemiological and genetic studies that have previously suggested a role for the immune system in AD. The emerging story affirms the likely role of innate and adaptive immune mechanisms in the pathogenesis of AD, but provides a cautionary note as to the difficulties that are likely to face potential immunomodulatory therapies due to the dualistic beneficial and detrimental roles that immune mechanisms appear to play in AD.
Alzheimer Disease↗
[Immune modulation with Kanne-Brottrunk to prevent pollinosis: a 1-year observational study with follow-up].
BACKGROUND: The immune enhancing properties of probiotics are scientifically well documented. Whether Kanne- Brottrunk (Selm-Bork, Germany) may play a preventive role in Pollinosis, was investigated in this study for the first time. PARTICIPANTS AND METHODS: 30 volunteers with pollinosis and a mean disease duration of 20 years agreed to consume 0.7 l Kanne-Brottrunk daily for one year. At the beginning and at the end of the study and one year later they retrospectively rated their pollinosis related quality of life during the previous pollinosis season with a disease specific questionnaire (FLQA: Freiburg Life Quality Assessment). Additionally, the change was rated directly and status was assessed in November 2002, January 2003, May 2003 and November 2003. RESULTS: 24 volunteers finished the study, although some of them consumed less than 0.7 l daily. 17 out of 20 assessed participants (85%) rated their pollinosis in the treatment year as 'very much better' or 'much better' (57% in the follow-up year). In 2003, the FLQA showed clinically relevant effect sizes (0.85-2.29) and statistically significant improvements (p < 0.05) for all six scales. In 2004, the improvements were slightly less pronounced (effect sizes 0.89-1.53) and were statistically significant for 4 scales (p < 0.05). 12 patients reported a relevant reduction or cessation of medication and many reported improvements of other immune related conditions. CONCLUSIONS: The observed improvements under regular daily consumption of Kanne-Brottrunk were marked and statistically significant. A randomized controlled trial would be necessary to allow causal conclusions.
Adult↗
Possible mechanisms of immune modulation in chronic dermatophytoses: an in vitro study.
It has been suggested that patients with chronic superficial Trichophyton rubrum infection have defective cellular immunity to dermatophyte antigens. This may be due to a selective anergy to dermatophyte antigens or reflect the activity of dermatophyte-derived lymphocyte inhibitory factors. To explore these possibilities, we assessed lymphocyte transformation to a variety of recall antigens, including a cytoplasmic and exoantigen preparation of Trichophyton rubrum in 15 patients with chronic dermatophyte infection and 15 age- and sex-matched positive controls. In a duplicate set of experiments, autologous serum was replaced by heat-inactivated fetal calf serum. In addition, the direct effect of Trichophyton rubrum extracts on lymphoproliferation was assessed in vitro. Comparable lymphocyte transformation to each recall antigen was observed in patients and controls. Moreover, we found no evidence for a circulating dermatophyte-derived lymphocyte inhibitory factor in sera from patients with chronic superficial infection. A direct inhibitory effect of Trichophyton rubrum on lymphocyte proliferation to recall antigens was observed, however, at protein concentrations of > 10 micrograms/ml (exoantigen preparation) and > 25 micrograms/ml (cytoplasmic preparation). This inhibitory effect was rapidly reversible, not associated with loss of cell viability and maximal when added within 24 h of antigen to cultured lymphocytes. Class II MHC antigen HLA-DR, a surface marker of T-cell activation, was observed on inhibited lymphocytes co-cultured with antigen, suggesting the primary target for the inhibitory effect in vitro is the lymphocyte rather than the antigen-presenting cell.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Melatonin: immune modulation of spleen cells in young, middle-aged and senescent mice.
We examined the effects of melatonin on the immune response in aged mice in an in vitro model system. Spleen cells were removed from 2 month old, 11 month old, and 19 month old C57/BL6 male mice and incubated with melatonin concentrations ranging from 50 to 5000 ng melatonin/ml. All age groups demonstrated increased ability to proliferation in response to mitogenic stimulation when melatonin and mitogen were added at the same time, and we demonstrated that 11 month old and 19 month old mice exhibited a greater increase in proliferation response than the young 2 month old mice. We further examined whether this increased responsiveness was due to increased levels of IL-2 and found that while there was a significant age-dependent difference in the levels of IL-2 in the different age groups, melatonin had no effect on IL-2 levels in any age groups despite the fact that proliferation increased in all groups. The underlying mechanism of melatonin action is being investigated further.
Adjuvants, Immunologic↗
Maternal cell traffic bounds for immune modulation: tracking maternal H-2 alleles in spleens of baby mice by DNA fingerprinting.
We have previously reported that the immunization of pregnant mice with T-dependent antigens successfully induced suppression of the antigen-specific plaque-forming cell (PFC) response to the relevant antigens in the offspring. This suppression was not caused by the administered antigens, the antibodies produced by the pregnant mother, or lactational transfer, but was dependent on the presence of the intact maternal T cells. It was major histocompatibility complex (MHC)-restricted manner tolerance, which continued for at least one-sixth of the murine life. Traditionally, the placenta acts as a natural barrier, not allowing the cells to pass through. However, the results presented strongly suggested that maternal T cells pass through the placenta and subsequently induce tolerance. In this present study, we attempted to substantiate the presence of maternal cells in the fetal circulation through the use of molecular techniques. We found that a highly polymorphic microsatellite sequence within the class II Eb gene of the H-2 complex is useful for the molecular detection of various H-2 alleles. DNA polymorphic analysis was used for tracking maternal H-2 alleles in the spleens of baby mice. The main procedure involved polymerase chain reaction amplification and restriction fragment length polymorphism analysis of the DNA sequence encompassing the H-2-specific microsatellite from the genomic DNA of baby mice. The results indicated that maternal T cells of immunized pregnant mice cross the placenta into the fetus, eventually inducing antigen-specific immunological tolerance in the offspring.
Alleles↗
The role of nitric oxide in lung innate immunity: modulation by surfactant protein-A.
Surfactant protein A (SP-A) and alveolar macrophages are essential components of lung innate immunity. Alveolar macrophages phagocytose and kill pathogens by the production of reactive oxygen and nitrogen species. In particular, peroxynitrite, the reaction product of superoxide and nitric oxide, appears to have potent antimicrobial effects. SP-A stimulates alveolar macrophages to phagocytose and kill pathogens and is important in host defense. However, SP-A has diverse effects on both innate and adaptive immunity, and may stimulate or inhibit immune function. SP-A appears to mediate toxic or protective effects depending on the immune status of the lung. In contrast to mouse or rat cells, it has been difficult to demonstrate nitric oxide production by human macrophages. We have recently demonstrated that human macrophages produce nitric oxide and use it to kill Klebsiella pneumoniae. SP-A either stimulates or inhibits this process, depending on the activation state of the macrophage. Given its diverse effects on immune function, SP-A may prove to be an effective therapy for both infectious and inflammatory diseases of the lung.
Animals↗
[Principles of the immune modulation therapy against papilloma virus infections].
The aim of the study was to investigate the effect of Immudone on local immune responses of cervical mucous in patients with papilloma virus cervicitis. 80 women of reproductive age with chronic cervicitis, 60 women with no signs of infection and 70 bioptates obtained from the base of vaginal section of the cervix. Colposcopic, bacterioscopic, patho-histological and immunohistochemical investigations have been performed. After using of Immudone healing of ectopia was observed in the most of cases. As a result of local application of Immudone in patients with PVI in the tissue of cervix the rate of CD4+ cells was increased, expression of receptors of interleukin-2 was increased, CD4/CD8 ratio also increased, quantity of macrophages and natural killers was increased. Local sIgA synthesis was restored.
Administration, Intravaginal↗
Immune modulation by flaviviruses.
Flaviviruses cause pleomorphic disease with significant morbidity and mortality worldwide. Interestingly, in contrast to most viruses, which subvert or avoid host immune systems, members of the neurotropic Japanese encephalitis serocomplex cause functional changes associated with increased efficacy of the immune response. These viruses induce increased cell surface expression of immune recognition molecules, including class I and II major histocompatibility complex (MHC) and various adhesion molecules. Increases are functional: infected cells are significantly more susceptible to both virus- and MHC-specific cytotoxic T cell lysis. Induced changes are modulated positively or negatively by Th1 and Th2 cytokines, as well as by cell cycle position and adherence status at infection. Infection also increases costimulatory molecule expression on Langerhans cells in the skin. Local interleukin-1 beta production causes accelerated migration of phenotypically altered Langerhans cells to local draining lymph nodes, where initiation of antiviral immune responses occur. The exact mechanism(s) of upregulation is unclear, but changes are associated with NF-kappa B activation and increased MHC and ICAM-1 gene transcription, independently of interferon (IFN) or other proinflammatory cytokines. Increased MHC and adhesion molecule expression may contribute to the pathogenesis of flavivirus encephalitis. Results from a murine model of flavivirus encephalitis developed in this laboratory suggest that fatal disease is immunopathological in nature, with IFN-gamma playing a crucial role. We hypothesize that these viruses may decoy the adaptive immune system into generating low-affinity T cells, which clear virus poorly, as part of their survival strategy. This may enable viral growth and immune escape in cycling cells, which do not significantly upregulate cell surface molecules.
Animals↗
Immune modulation of Prevotella intermedia colonization in squirrel monkeys.
Colonization of the gingival crevice by black-pigmented Porphyromonas or Prevotella spp. (BP/P), including Porphyromonas gingivalis (formerly Bacteroides gingivalis) and Prevotella intermedia (formerly Bacteroides intermedius), is thought to be an important ecological event which may result in the destruction of connective tissues supporting the teeth. Theoretically, periodontal diseases could be prevented if these or other periodontal pathogenic microorganisms did not colonize the subgingival area. The humoral immune response is one mechanism which may modulate bacterial colonization in the gingival crevice. In the present study, we tested the effect of systemic humoral immunity on subgingival colonization by indigenous P. intermedia in squirrel monkeys (Saimiri sciureus). Animals rendered essentially free of detectable BP/P by a single scaling, 10 days of tetracycline therapy, and toothbrushing three times per week were immunized with P. intermedia 1447 or were sham immunized with phosphate-buffered saline. Subsequently, all oral hygiene procedures were discontinued and five teeth in one quadrant were ligated with bacterium-soaked suture material to facilitate BP/P colonization. Immunization resulted in a significant increase in the level of immunoglobulin G anti-P. intermedia antibody in serum. Two weeks after ligation was initiated, P. intermedia could be detected in five of six sham-immunized and three of six immunized animals. Immunization was associated with a reduction in the emergence of indigenous P. intermedia in the gingival crevice.
Animals↗
Immune modulation and apoptosis induction: two sides of the antitumoral activity of imiquimod.
Imiquimod, the first member of the imidazoquinoline family of immune response modifiers, has proven good clinical efficacy against basal cell carcinomas and actinic keratoses in several independent studies. In addition, there is recent evidence that imiquimod is also efficacious against other tumors such as cutaneous metastases of malignant melanoma or vascular tumors. Imiquimod exerts its antitumoral effect, at least in part, through binding to TLR-7 and TLR-8 on dendritic cells followed by secretion of a multitude of proinflammatory cytokines. The net result of this proinflammatory activity is a profound tumor-directed cellular immune response. However, recent experimental and clinical data indicate that imiquimod also possesses considerable direct pro-apoptotic activity against tumor cells both in vitro and in vivo. This novel mode of action appears to be independent of membrane bound death receptors, but involves caspase activation. Induction of apoptosis by imiquimod is, at least in part, presumably mediated through Bcl-2-dependent release of mitochondrial cytochrome c and subsequent activation of caspase-9. The structural analogue, resiquimod, exhibited very limited, if any, such pro-apoptotic activity, possibly due to its lacking ability to enter the cell. Bypassing molecular mechanisms of apoptosis deficiency by a topical compound may be of great utility for treating certain cutaneous tumors.
Adjuvants, Immunologic↗
Targeting with scFv: immune modulation by complement receptor specific constructs.
The fate of a microbe in the host is determined by various molecules of the innate immune system, which recognize the microbe and enhance its interaction with antigen presenting cells. This 'natural targeting' phenomenon, however, does not function when antigens with limited immunogenicity enter the host. Peptide vaccines, for instance, require adjuvants to induce immune responses. As a surrogate for the natural targeting mechanisms, antibodies against selected receptors of antigen presenting cells, conjugated with the peptides, could be used as targeting devices. Here we review various antibody-mediated antigen-targeting strategies, paying special attention to complement receptor-mediated targeting. We also describe and summarize our method of single-chain antibody-mediated targeting of viral epitopes to complement receptor type two and discuss the perspectives of single-chain antibody-mediated antigen targeting.
Adjuvants, Immunologic↗