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At least 685 records · Page 38Linked to original sources
PubMed1996

Adenovirus-mediated gene transfer in the transplant setting: early events after orthotopic transplantation of liver allografts expressing TGF-beta1.

We hypothesized that adenovirus mediated gene transfer of TGF-beta1 into liver grafts would enhanced local expression of this recombinant protein and down-regulate inflammatory and alloreactive immune response. A full length DNA encoding the murine TGF-beta1 was used to replaced the E1 region of adenovirus type 5 (AdmTGF-beta1). Expression and protein production of biologically active murine TGF-beta1 was tested in AdmTGF-beta1-transduced Hep G2 cells and TGF-beta-sensitive MV1 cells. In the transplant setting, the replication-defective vector was used to perfused cold preserved ACI liver allograft prior to transplantation into Lewis recipients. Control livers were similarly perfused with cold lactated Ringer's solution and were followed without immunosuppression. Animals were sacrificed at 1, 3, and 5 days after transplantation. Intragraft cytokine levels of TNFalpha, and IFNgamma were determined using ELISA and quantitative PCR. TGF-beta1 ELISA of culture supernatants from AdmTGF-beta1 transduced hepatocyte cell line Hep G2 excreted TGF-beta1 in quantities directly correlated with multiplicity of infection (MOI, vector:hepatic cell ratio). The biological activity of the excreted recombinant protein was confirmed by growth inhibition of MV1 TGF-beta-sensitive cells. Enhanced production of TGF-beta1 in transduced allografts was associated with decreased levels of TNFalpha and IFNgamma when compared with nonimmunosuppressed controls. Adenovirus-mediated gene transfer of murine TGF-beta1 into hepatic cells results in the expression of biologically active protein. Transduction of allografts with TGF-beta1 down-regulates TNFalpha and IFNgamma production early after orthotopic transplantation. Graft transduction with TGF-beta1 offers a novel approach to study the effects of single immune modulator on alloreactive immune response, T cell function, and cytokine cascade.

Adenoviridae↗
PubMed1992

The effect of non-immune IgG on antigen-antibody complexation.

Two preparations of human IgG, one acylated with beta-propiolactone (acylated IgG) and one treated at pH 4 with traces of pepsin (pH 4-IgG), were used to study the effect of non-immune IgG on antigen-antibody interactions in the antigen excess zone. Employing two immunological methods together with size-exclusion chromatography, we found that the formation of human albumin-rabbit anti-human albumin complexes was inhibited in the presence of human IgG. In addition, IgG seemed to promote the aggregation of already formed complexes. Thus, non-immune IgG may modulate immune complexation by direct molecular interactions. The effect was dependent on the size and composition of the immune complexes as well as on the conformation of the IgG molecules with respect to their shape, isotype, charge, and other surface properties. Some possible mechanisms for the reactions are discussed.

Acylation↗
PubMed1989

Transfusion history, T cell subsets and natural killer cytotoxicity in patients with colorectal cancer.

Blood transfusions are associated with clinical phenomena which are attributable to immune suppression. Since suppression of immune function is associated with a high risk of spontaneous malignancies, we studied T cell subsets and natural killer (NK) cytotoxicity in colorectal cancer patients and correlated the results with patients' transfusion histories. Twelve percent (14) of the 115 patients had been transfused an average of 19 years previously. Recipients of blood transfusions had low levels of peripheral lymphocytes (p = 0.191), T cells (p = 0.015), helper cells (p = 0.016) and suppressor cells (p = 0.2651) compared to previously untransfused patients. NK cytotoxicity was also significantly reduced in transfusion recipients although NK cell numbers were comparable in both groups. These results support previous studies indicating that blood transfusions cause lifelong immune modulation in the recipient. Since blood transfusions have numerous beneficial effects and immune modulation is often beneficial, longitudinal studies are necessary to define the lifetime risks and benefits.

Aged↗
PubMed2006

Reduced protective efficacy of a blood-stage malaria vaccine by concurrent nematode infection.

Helminth infections, which are prevalent in areas where malaria is endemic, have been shown to modulate immune responses to unrelated pathogens and have been implicated in poor efficacy of malaria vaccines in humans. We established a murine coinfection model involving blood-stage Plasmodium chabaudi AS malaria and a gastrointestinal nematode, Heligmosomoides polygyrus, to investigate the impact of nematode infection on the protective efficacy of a malaria vaccine. C57BL/6 mice immunized with crude blood-stage P. chabaudi AS antigen in TiterMax adjuvant developed strong protection against malaria challenge. The same immunization protocol failed to induce strong protection in H. polygyrus-infected mice. Immunized nematode-infected mice produced significantly lower levels of malaria-specific antibody than nematode-free mice produced. In response to nematode and malarial antigens, spleen cells from immunized nematode-infected mice produced significantly lower levels of gamma interferon but more interleukin-4 (IL-4), IL-13, and IL-10 in vitro than spleen cells from immunized nematode-free mice produced. Furthermore, H. polygyrus infection also induced a strong transforming growth factor beta1 response in vivo and in vitro. Deworming treatment of H. polygyrus-infected mice before antimalarial immunization, but not deworming treatment after antimalarial immunization, restored the protective immunity to malaria challenge. These results demonstrate that concurrent nematode infection strongly modulates immune responses induced by an experimental malaria vaccine and consequently suppresses the protective efficacy of the vaccine against malaria challenge.

Adjuvants, Immunologic↗
PubMed2004

Receptor-dependent coronavirus infection of dendritic cells.

In several mammalian species, including humans, coronavirus infection can modulate the host immune response. We show a potential role of dendritic cells (DC) in murine coronavirus-induced immune modulation and pathogenesis by demonstrating that the JAW SII DC line and primary DC from BALB/c mice and p/p mice with reduced expression of the murine coronavirus receptor, murine CEACAM1a, are susceptible to murine coronavirus infection by a receptor-dependent pathway.

Animals↗
PubMed2005

Inhibition of toll-like receptor 7- and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus.

Human plasmacytoid dendritic cells (PDC) are key sentinels alerting both innate and adaptive immune responses through production of huge amounts of alpha/beta interferon (IFN). IFN induction in PDC is triggered by outside-in signal transduction pathways through Toll-like receptor 7 (TLR7) and TLR9 as well as by recognition of cytosolic virus-specific patterns. TLR7 and TLR9 ligands include single-stranded RNA and CpG-rich DNA, respectively, as well as synthetic derivatives thereof which are being evaluated as therapeutic immune modulators promoting Th1 immune responses. Here, we identify the first viruses able to block IFN production by PDC. Both TLR-dependent and -independent IFN responses are abolished in human PDC infected with clinical isolates of respiratory syncytial virus (RSV), RSV strain A2, and measles virus Schwarz, in contrast to RSV strain Long, which we previously identified as a potent IFN inducer in human PDC (Hornung et al., J. Immunol. 173:5935-5943, 2004). Notably, IFN synthesis of PDC activated by the TLR7 and TLR9 agonists resiquimod (R848) and CpG oligodeoxynucleotide 2216 is switched off by subsequent infection by RSV A2 and measles virus. The capacity of RSV and measles virus of human PDC to shut down IFN production should contribute to the characteristic features of these viruses, such as Th2-biased immune pathology, immune suppression, and superinfection.

Dendritic Cells↗
PubMed2005

Nitric oxide inhibits IFN-alpha production of human plasmacytoid dendritic cells partly via a guanosine 3',5'-cyclic monophosphate-dependent pathway.

NO, a free radical gas, is known to be critically involved not only in vascular relaxation but also in host defense. Besides direct bactericidal effects, NO has been shown to inhibit Th1 responses and modulate immune responses in vivo, although the precise mechanism is unclear. In this study, we examined the effect of NO on human plasmacytoid dendritic cells (pDCs) to explore the possibility that NO might affect innate as well as adaptive immunity through pDCs. We found that NO suppressed IFN-alpha production of pDCs partly via a cGMP-dependent mechanism, which was accompanied by down-regulation of IFN regulatory factor 7 expression. Furthermore, treatment of pDCs with NO decreased production of IL-6 and TNF-alpha and up-regulated OX40 ligand expression. In accordance with these changes, pDCs treated with NO plus CpG-oligodeoxynucleotide AAC-30 promoted differentiation of naive CD4(+) T cells into a Th2 phenotype. Moreover, pDCs did not express inducible NO synthase even after treatment with AAC-30, LPS, and several cytokines. These results suggest that exogenous NO and its second messenger, cGMP, alter innate as well as adaptive immune response through modulating the functions of pDCs and may be involved in the pathogenesis of certain Th2-dominant allergic diseases.

Antigens, Surface↗
PubMed2006

Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis.

In the setting of autoimmunity, one of the goals of successful therapeutic immune modulation is the induction of peripheral tolerance, a large part of which is mediated by regulatory/suppressor T cells. In this report, we demonstrate a novel immunomodulatory mechanism by an FDA-approved, exogenous peptide-based therapy that incites an HLA class I-restricted, cytotoxic suppressor CD8+ T cell response. We have shown previously that treatment of multiple sclerosis (MS) with glatiramer acetate (GA; Copaxone) induces differential up-regulation of GA-reactive CD8+ T cell responses. We now show that these GA-induced CD8+ T cells are regulatory/suppressor in nature. Untreated patients show overall deficit in CD8+ T cell-mediated suppression, compared with healthy subjects. GA therapy significantly enhances this suppressive ability, which is mediated by cell contact-dependent mechanisms. CD8+ T cells from GA-treated patients and healthy subjects, but not those from untreated patients with MS, exhibit potent, HLA class I-restricted, GA-specific cytotoxicity. We further show that these GA-induced cytotoxic CD8+ T cells can directly kill CD4+ T cells in a GA-specific manner. Killing is enhanced by preactivation of target CD4+ T cells and may depend on presentation of GA through HLA-E. Thus, we demonstrate that GA therapy induces a suppressor/cytotoxic CD8+ T cell response, which is capable of modulating in vivo immune responses during ongoing therapy. These studies not only explain several prior observations relating to the mechanism of this drug but also provide important insights into the natural immune interplay underlying this human immune-mediated disease.

Adult↗
PubMed2001

Macrophage migration inhibitory factor (MIF) modulates innate immune responses induced by endotoxin and Gram-negative bacteria.

Discovered in the early 1960s as a T-cell cytokine, MIF has emerged to be an important mediator of the innate immune system. MIF was identified recently to be released by a vast array of cells, including monocytes/macrophages, T-cells, B-cells, endocrine cells and epithelial cells in response to infection and stress. Bacteria, microbial toxins and cytokines have been shown to be powerful inducers of MIF secretion by macrophages. MIF stimulates the expression of pro-inflammatory mediators by immune cells and functions to counterbalance the anti-inflammatory and immunosuppressive effects of glucocorticoids. Like TNF and IL-1, MIF plays an important role in host responses to infection. Recombinant MIF was found to exacerbate lethal endotoxemia or bacterial sepsis when co-injected with LPS or Escherichia coli in mice. Conversely, MIF knockout mice or mice treated with anti-MIF antibodies were protected from shock induced by LPS, staphylococcal exotoxins or bacterial peritonitis, even when anti-MIF therapy was started after the onset of infection. Given the central role played by MIF in innate immune responses against microbial pathogens and in the regulation of inflammatory responses, pharmacological modulation of MIF production or neutralization of MIF activity could have broad clinical applications and may offer new treatment options for the management of patients with severe sepsis or septic shock.

Animals↗
PubMed1997

Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo.

Herpesviruses, such as murine and human cytomegalovirus (MCMV and HCMV), can establish a persistent infection within the host and have diverse mechanisms as protection from host immune defences. Several herpesvirus genes that are homologous to host immune modulators have been identified, and are implicated in viral evasion of the host immune response. The discovery of a viral major histocompatibility complex (MHC) class I homologue, encoded by HCMV, led to speculation that it might function as an immune modulator and disrupt presentation of peptides by MHC class I to cytotoxic T cells. However, there is no evidence concerning the biological significance of this gene during viral infection. Recent analysis of the MCMV genome has also demonstrated the presence of a MHC class I homologue. Here we show that a recombinant MCMV, in which the gene encoding the class I homologue has been disrupted, has severely restricted replication during the acute stage of infection compared with wild-type MCMV. We demonstrate by in vivo depletion studies that natural killer (NK) cells are responsible for the attenuated phenotype of the mutant. Thus the viral MHC class I homologue contributes to immune evasion through interference with NK cell-mediated clearance.

Amino Acid Sequence↗
PubMed2001

Mast cell modulation of immune responses to bacteria.

Mast cells are key elements of the immune system. These cells release a wide variety of pro-inflammatory mediators which are responsible for the pathophysiology of many allergic diseases. Recent studies, however, have shown that mast cells have the capacity to modulate the host's innate immune response to gram negative bacteria by their ability to phagocytose bacteria, process and present bacterial antigens to T cells and recruit phagocytic help through the release of physiological amounts of pro-inflammatory mediators. Here, current knowledge of mast cell responses to gram negative bacteria and molecular mechanisms associated with mast cell bacteria interaction is reviewed.

Acetamides↗
PubMed1993

Direct innervation of lymphoid organs: substrate for neurotransmitter signaling of cells of the immune system.

The nervous system can generate outflow capable of signaling cells of the immune system via two routes: (1) hormonal influences via hypothalamopituitary-target organ activation, and (2) neurotransmitter influences via direct innervation of the parenchyma of both primary and secondary lymphoid organs. Both noradrenergic and neuropeptidergic nerve fibers are found directly adjacent to cells of the immune system in bone marrow, thymus, spleen, lymph nodes, and other sites. These neurotransmitters can modulate immune responsiveness at several levels, including individual cellular functions, collective cellular interactions and immune responses, and overall host immunological response to a challenge by bacteria, viruses, tumor cells, or other sources. The ability of neural signals to modulate immune responsiveness is influenced by such factors as co-localization with other neurotransmitters, synergistic or dual signaling by neurotransmitters and cytokines, hormonal influences on ligand availability or receptor responsiveness, extent of catabolism and inactivation of the neural signal, and unique chemical and morphological aspects of the specific compartmentation of the lymphoid organ in which signaling is taking place. Thus, neural-immune signaling is a complex and dynamic process, with bidirectional interactions in a complex microenvironment.

Animals↗
PubMed2004

Infliximab therapy for sarcoidosis (lupus pernio).

Sarcoidosis is a chronic granulomatous disease of unknown aetiology in which the primary cytokine tumour necrosis factor (TNF)-alpha appears to play a major role. Older immune-modulating drugs including corticosteroids, antimalarials and thalidomide, as well as cytotoxic drugs with immune modulatory effects, have been used to control disease. We present a patient with severe mutilating cutaneous sarcoidosis (lupus pernio) who had showed only partial response to courses of a wide spectrum of immune modulators and cytotoxic therapies, and who had developed significant side-effects due to prolonged high-dose corticosteroids. However, the patient's cutaneous disease responded rapidly to the TNF-alpha inhibitor infliximab.

Adult↗
PubMed2005

The immunological effect of photopheresis in children with newly diagnosed type 1 diabetes.

Photopheresis has been claimed to have immune-modulating effects, but the mechanisms of action are unknown. This study investigated the immune effect of photopheresis in children with type 1 diabetes, with a focus on the balance of Th1- and Th2-like cytokines. Ten children with newly diagnosed type 1 diabetes (10-17 y) were treated with five double treatments of photopheresis and 10 children matched for disease, age, and gender were given placebo tablets and sham pheresis. Expression of IFN-gamma and IL-4 mRNA was determined by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and secretion of IFN-gamma, IL-10, and IL-13 in cell-culture supernatants by ELISA after stimulation with glutamic acid decarboxylase (GAD65) (a.a. 247-279), the ABBOS peptide (a.a. 152-169), insulin, phytohemagglutinin (PHA), and keyhole limpet hemocyanin (KLH). Photopheresis changed antigen-stimulated immune balance in line with a Th2-like shift. Thus, the ratio of IFN-gamma/IL-4 mRNA expression after in vitro stimulation with a peptide of the autoantigen GAD65 was reduced after treatment in the photopheresis group. The IFN-gamma/IL-4 mRNA expression ratio after in vitro stimulation with insulin was also lower in children treated with photopheresis compared with the placebo group. Photopheresis has an immune-modulating effect in children with type 1 diabetes, causing a Th2-like deviation.

Adolescent↗
PubMed2006

State of the art. Four easy pieces: interconnections between tissue injury, intermediary metabolism, autoimmunity, and chronic degeneration.

Four questions are posed: (1) Can tissue damage itself provoke autoimmunity? (2) Can genetic mutations of key structures produce tissue pathology and thus provoke autoimmunity? (3) Can acute immune damage produce tissue degeneration without further hallmarks of an immune response? (4) Can intermediary metabolism modulate immune damage to tissues? Four answers are given: (1) Tissue injury itself may lead to autoimmunity. Both innate and adaptive immunity may arise as a response to tissue injury, and the immune attack can further damage tissue. (2) Genetic mutations can lead to an immune response indistinguishable from autoimmunity, exemplified from Duchenne's Muscular Dystrophy and X-linked adrenoleukodystrophy. (3) Chronic immune damage may lead to tissue degeneration, with or without further hallmarks of an immune response. Variations on this theme, including inverse scenarios, are also possible: Inborn errors of metabolism may lead to tissue damage that may provoke an adaptive and or innate immune response. The immune response might further damage tissue. (4) Finally, perturbations of intermediary metabolism may modulate the immune response, controlling the extent of immune-mediated damage. Examples are taken from perturbations in the cholesterol pathway that influence the characteristics of the immune response, and with tryptophan metabolites that modulate autoimmunity and graft rejection. Inflammatory, degenerative, and autoimmune neurological disease will be discussed in terms of their implications for pathogenic mechanisms underlying chronic obstructive pulmonary disease.

Adrenoleukodystrophy↗
PubMed2006

The Drosophila amidase PGRP-LB modulates the immune response to bacterial infection.

The Drosophila host defense against gram-negative bacteria is mediated by the Imd pathway upon sensing of peptidoglycan by the peptidoglycan recognition protein (PGRP)-LC. Here we report a functional analysis of PGRP-LB, a catalytic member of the PGRP family. We show that PGRP-LB is a secreted protein regulated by the Imd pathway. Biochemical studies demonstrate that PGRP-LB is an amidase that specifically degrades gram-negative bacteria peptidoglycan. In agreement with its amidase activity, PGRP-LB downregulates the Imd pathway. Hence, activation of PGRP-LB by the Imd pathway provides a negative feedback regulation to tightly adjust immune activation to infection. Our study also reveals that PGRP-LB controls the immune reactivity of flies to the presence of ingested bacteria in the gut. Our work highlights the key role of PGRPs that encode both sensors and scavengers of peptidoglycan, which modulate the level of the host immune response to the presence of infectious microorganisms.

Animals↗
PubMed1989

Modulation of immunity in patients with autoimmune disease and cancer treated by extracorporeal immunoadsorption with PROSORBA columns.

Extensive animal studies and clinical observations support an immunosuppressive role for certain antibodies and circulating immune complexes (CIC) in malignant and autoimmune diseases. Investigators have attempted to correct or modulate dysfunction by removal of antibodies or CIC from plasma. Extra-corporeal immunoadsorption of plasma over columns containing a silica matrix and covalently attached highly purified staphylococcal protein A (PROSORBA column) is a procedure that specifically removes those plasma components by the interaction of protein A with the Fc region of IgG. The interaction of CIC with the Fc receptor on protein A has three specific results. First, there is direct removal of immunosuppressive CIC from the circulation. Studies of CIC-mediated immunosuppression in experimental systems have shown dose-response relationships over wide ranges of CIC concentrations. Thus, removal of CIC relative to the IgG antibody may be expected to exert some stimulation of the immune system. Second, the complement system is activated. Elevated levels of C3a, C4a, and C5a are observed in patients' circulating plasma after PROSORBA treatment. These levels peak one to three hours post-perfusion and are near normal levels by six hours post-perfusion. These complement components are stimulators of growth and activity of immune cells. In addition, by binding to CIC they stimulate clearance of CIC by the reticuloendothelial system. Thus, treatments may induce removal of more CIC than could be anticipated by the binding capacity of treatment columns. Third, antibody is released from CIC. Interaction of CIC with bound protein A with or without the aid of activated complement components leads to liberation of free antibody. Depending upon other factors, eg, amount of circulating antigen and/or unbound IgG, either free antibody or CIC containing more antibody relative to antigen (or both) may be infused into patients with the posttreatment plasma. Such CIC function as immune stimulators rather than suppressors of immune cell activity. The consequences of the treatments are summarized as follows. Stimulation of immune cellular activity is seen one to three hours posttreatment. During the first one to three treatments, cells of the granulocyte/macrophage series show the greatest increase. During and after treatments 2 to 4, lymphocytes show the greatest increase. At this point, increased blastogenic response to mitogens is observed along with an increase in the T helper/suppressor cell ratio.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗