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PubMed2003

Safety of CpG oligodeoxynucleotides in veterinary species.

Bacterial DNA and synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs in particular sequence contexts (CpG ODN) are recognized as a danger signal by the innate immune system of vertebrates. For this reason, CpG ODNs have a potential application as both an adjuvant and nonspecific immune modulator and are currently being evaluated in a number of human and veterinary clinical trials. Given their potent immunostimulatory activity, CpG ODNs could possibly induce adverse reactions. As all adjuvants and immune modulators must be nontoxic to meet safety requirements, it was essential to address the safety aspects of CpG ODNs. The current review summarizes experiments carried out to date to establish the safety of CpG ODNs in animals.

Adjuvants, Immunologic↗
PubMed1987

Modulation of immune function in cancer patients.

This paper will focus on three aspects of work which we have conducted in our laboratory over the past several years. Firstly, it will present results of studies in which we have found a selective inhibition of suppressor cell function in solid tumor cancer patients treated with cytotoxic drugs. Secondly, it will show that this selective inhibition results in an augmentation of other forms of immune reactivity and, in particular, an enhanced interleukin-2 production and response to this. Finally, it will demonstrate how we have made use of that information to intervene pharmacologically to modulate the immunosuppression which usually follows the use of cytotoxic drugs in solid tumor cancer patients.

Antineoplastic Agents↗
PubMed2005

Toll-like receptor ligands as adjuvants in allergen-specific immunotherapy.

BACKGROUND: Allergen-specific immunotherapy (SIT) leads to long-term amelioration of T-helper type 2 (Th2)-mediated allergic symptoms and is therefore recommended as a first line therapy for allergies. The major disadvantage of SIT is its low efficiency, requiring treatment over years. OBJECTIVE: In this study, we evaluated the potential of Toll-like receptor (TLR) ligands to facilitate Th1-type immune responses. METHODS: The immunogenicity and therapeutic potential of the major bee venom allergen phospholipase A2 (PLA2) combined with various TLR ligands were tested in mice and compared with immune responses induced by conventional aluminium-based preparations. RESULTS: Regarding total IgG against PLA2, TLR2/4-binding lipopolysaccharide and TLR3-binding polyriboinosinic polyribocytidylic (PolyI:C) were the superior adjuvants for prophylactic vaccination. However, TLR9-binding phosphorothioate-modified cytosine-guanosine-rich oligonucleotide (CpG), TLR-3-binding PolyI:C, and TLR2/6-binding peptidoglycan skewed the immune responses more towards IgG2a isotype and Th1 cytokines. Furthermore, in a therapeutic approach, CpG, PolyI:C and TLR7/8-binding 3M003 had immune modulating properties as they suppressed established IgE titres. CONCLUSION: The potential of TLR ligands to adjuvate the immunogenicity of bee venom PLA2 and to skew the Th1-Th2 balance proved very heterogeneous. With respect to SIT, CpG, PolyI:C, and 3M003 were very promising. Hence, TLR ligands should be considered as adjuvants or immune modulators in SIT in human as to improve its efficiency regarding the Th1-Th2 balance of the immune response with a likely effect on therapy duration.

Adjuvants, Immunologic↗
PubMed1996

One step ahead of the game: viral immunomodulatory molecules.

For decades cell biologists have relied on viruses to facilitate the study of complex cellular function. More recently, the tragedy of the AIDS epidemic has focused considerable human and financial resources on both virology and immunology, resulting in the generation of new information relating these disciplines. As the miracle of the mammalian immune system unfolds in the laboratory, the elegance of the mechanisms used by co-evolving viruses to circumvent detection and destruction by the host becomes inescapably obvious. Although many observation of virus-induced phenomena that likely contribute to the virus's escape of immune surveillance are still empirical, many other such phenomena have now been defined at the molecular level and confirmed in in vivo models. Immune modulators encoded within viral genomes include proteins that regulate antigen presentation, function as cytokines or cytokine antagonists, inhibit apoptosis, and interrupt the complement cascade. The identification of such gene products and the elucidation of their function have substantially strengthened our understanding of specific virus-host interactions and, unexpectedly, have contributed to the recognition of potent synergy between viruses, which can result in an unpredictable exacerbation of disease in co-infected individuals. Because many viral immune modulators clearly have host counterparts, viruses provide a valuable method for studying normal immune mechanisms. It is conceivable that an improved understanding of virus-encoded immunomodulators will enhance our ability to design reagents for use in therapeutic intervention in disease and in vaccine development.

Adjuvants, Immunologic↗
PubMedDate not supplied

Review of autoimmune (lupus-like) glomerulonephritis in murine models.

While murine models of autoimmune (lupus-like) glomerulonephritis have been available for sometime, it is only recently that immune and inflammatory mechanisms and molecular genetics have been extensively investigated. Genes involved in murine and human lupus nephritis have been discovered and provide insight into this disease process and provide avenues for molecular-targeted therapy. Immune modulation of murine nephritis has provided insight into novel therapy that may attenuate this disease or halt disease progression. With the advances in understanding the pathogenesis of lupus nephritis using translational research modalities, including electron microscopy, and molecular genetics, many "designer" therapies have become available for clinical use and for clinical investigational trials. This paper reviews autoimmune (lupus-like) glomerulonephritis in murine models, candidate genes involved in lupus nephritis, adhesion molecules implicated in murine lupus-like nephritis, immune modulation of murine lupus-like nephritis, and novel and potential therapy for immune complex glomerulonephritis.

Animals↗
PubMed2005

Antioxidant enzyme activities of human peripheral blood mononuclear cells exposed to trace elements.

The trace elements copper, zinc, and selenium are important immune modulators and essential cofactors of the antioxidant enzymes. In the present study, the proliferative effect of human peripheral mononuclear cells (PBMCs) that have been exposed to copper, zinc, and selenium and the corresponding activities of antioxidant enzymes, namely superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase, were determined. Zinc and copper stimulated the PBMC proliferation in a dose-dependent manner within the dose range 25-200 micromol/L. SOD and GPx activities in PBMCs exposed to zinc were inhibited, whereas catalase activity was unaffected. All the three antioxidant enzymes in the cells exposed to copper were inhibited. Selenium exerted more potent inhibition of the cell proliferation while causing stimulation of the antioxidant enzymes at the lowest dose (25 micromol/L) than at the highest dose (200 micromol/L) tested. A significant negative correlation was observed between proliferation and antioxidant enzyme (SOD and GPx) activities in trace-element-exposed PBMC. The present findings substantiate the importance of trace elements as immune modulators and the involvement of enzymatic antioxidant system in the immune cell regulation.

Antioxidants↗
PubMed1990

Circulating immune complexes detected by a direct nephelometric assay and acute phase proteins in malignant tumors.

Circulating immune complexes (CIC) were previously reported to be higher in extended cancer rather than in localized one, by a few groups of investigators as well as by ourselves. The techniques employed were quite different in each study. We described a "direct" laser nephelometric assay. At the same time we determined the serum levels of 4 acute phase proteins (AFP)--alpha 2 macroglobulin, C reactive protein, haptoglobin, alpha 1 acid glycoprotein--by conventional light scattering method, in order to investigate on other possible "immune-modulating" factors. The possible correlations either with prognosis or clinical stage are looked for; the hypothetical behaviour of CIC as one of the serum "blocking factors" and of acute phase reactant as "immune modulating" proteins are discussed. The data concerning the techniques able to remove CIC from the blood stream of the cancer patients were also showed (plasmapheresis and immunoadsorption).

Acute-Phase Proteins↗
PubMed1990

Regulation of renal transport processes and hemodynamics by macrophages and lymphocytes.

Inflammatory diseases of the renal glomerulus and interstitium are characterized by numerous alterations in renal glomerular hemodynamics and tubule transport processes. The cellular mechanisms underlying these changes have been theoretically attributed to nephron toxicity and destruction. However, recent studies suggest that many of the alterations in renal physiology may be mediated by specific immune cell-derived factors. Macrophages release a variety of cytokines on activation. One of these monokines, interleukin 1, induces a natriuresis by direct inhibition of collecting duct sodium reabsorption. Glomerular macrophages release highly vasoconstrictive compounds, including leukotriene D4 and thromboxane A2. Macrophages have now been demonstrated to migrate into the renal interstitium in diseases not previously considered to have an immunological component. Acute ureteral obstruction is characterized by a rapid infiltration of macrophages and lymphocytes into the kidney. Removal of the immune cell infiltrate in ureteral obstruction by irradiation markedly improves glomerular filtration rate and renal blood flow and partially corrects sodium and water excretion. Such immune modulation of renal function is likely to occur in a wide variety of diseases of the kidney, many of which do not involve a primary immunological insult. We propose that the abnormalities in renal hemodynamics and in the transport of fluid and electrolytes observed in states characterized by coexistence of immune cells among renal parenchymal cells may reflect a complex immune modulation of renal cell physiology.

Animals↗
PubMed1997

Transfusion in HIV disease.

Cytopenias often accompany infection with HIV. The pathophysiology responsible for the anemia, neutropenia, and thrombocytopenia in AIDS is complex and incompletely understood. Although HIV-infected patients with advanced disease were once routinely transfused for anemia accompanying zidovudine therapy, this practice has decreased as a result of decreased doses of zidovudine now being used and the more frequent use of HIV protease inhibitors. A more thorough understanding of the adverse effects of transfusion and the potential of immune modulation and facilitation of viral replication has no doubt led physicians to consider more thoroughly other factors before transfusing their patient. The results of trials examining the effect of leukodepletion on transfusion-related immune modulation are eagerly awaited. The availability of hematopoietic growth factors has also led to more effective treatment of the cytopenias without significant complications.

AIDS-Related Opportunistic Infections↗
PubMed2006

Heligmosomoides polygyrus induces TLR4 on murine mucosal T cells that produce TGFbeta after lipopolysaccharide stimulation.

Helminths are immune modulators that down-regulate colitis in inflammatory bowel disease. In animal models, intestinal bacteria drive colitis and in humans certain alleles of the LPS receptor protein TLR4 increase inflammatory bowel disease susceptibility. To understand helminthic immune modulation in the gut, we studied the influence of intestinal Heligmosomoides polygyrus colonization on LPS-induced lamina propria mononuclear cell (LPMC) cytokine responses in mice. LPS did not stimulate TGFbeta production from LPMC of uninfected mice. LPS strongly induced LPMC from worm-infected animals to secrete TGFbeta, but not TNF-alpha or IL-12. The TGFbeta derived from mucosal T cells. Helminth infection up-regulated TLR4 expression only in lamina propria T cells. LPMC from worm-infected TLR4 mutant animals did not respond to LPS, suggesting that LPS required TLR4 to stimulate TGFbeta secretion. Thus, during helminth infection, LPS challenge induces mucosal T cells to make TGFbeta through a TLR4-dependent process without promoting synthesis of proinflammatory cytokines.

Animals↗
PubMed2006

Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment.

OBJECTIVES: To examine the immune modulating effects of cyclooxygenase type 2 (COX-2) inhibitors (COX-2i) in HIV-infected patients on combination antiretroviral treatment (CART). DESIGN: In-depth substudy from an approved, open, controlled, randomized study comparing the immune modulating effects of CART in combination with COX-2i after 12 weeks. METHODS: Patients (n = 38) on long-term CART with stable viral load (VL) < 50,000 copies/ml and CD4+ T-cell counts > 100/microl were randomized to CART and rofecoxib 25 mg bid (n = 12) or celecoxib 400 mg bid (n = 12), or CART only without placebo (n = 14). Routine clinical chemistry, CD4+ and CD8+ counts and VL were safety parameters. Immunological parameters included C-reactive protein, beta2-microglobulin, Ig isotypes and IgG subclasses as well as several T-lymphocyte subsets. Non-parametric analyses were used throughout. RESULTS: Prestudy experiments showed higher median intracellular expression of COX-2 in CD4+ (P = 0.048) and possibly CD8+ (P = 0.09) T cells from patients on CART compared with uninfected controls. In the clinical study, increased CD4+ T-cell counts were observed only in patients on COX-2i with VL < 50 copies/ml (P = 0.02). Decreased expression of CD38+ on CD8+ T cells and subsets as well as reductions in IgA and IgM (P < 0.03) were most pronounced in patients on COX-2i who had detectable VL (n = 6). COX-2i treatment enhanced the perforin content particularly in the differentiated CD27-/CD8+ T-cell subsets compared with controls (P = 0.05). CONCLUSIONS: COX-2i together with CART improved markers for persistent immune activation, particularly in patients with viraemia, as well as enhanced perforin expression, and thereby strengthened COX-2 as a potential therapeutic target in HIV infection.

ADP-ribosyl Cyclase 1↗
PubMed2004

The role of intrahepatic CD8+ T cell trapping and NK1.1+ cells in liver-mediated immune regulation.

UNLABELLED: The liver was previously suggested as a site of lymphocyte clearance. Liver-associated lymphocytes that express NK1.1 marker (NKT LAL) play a role in immune modulation. AIM: To determine the role of the liver and of NKT LAL in determining the CD4+/CD8+ balance during tolerance induction. METHODS: Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Immune tolerance was induced via five oral feedings of colitis-extracted proteins (CEP) from TNBS-colitis colonic wall, starting on the day of colitis induction (group A). Control mice were fed with BSA (group B). To determine the role of NKT cells in immune modulation, NK1.1 depletion was performed in nonfed (group C) and fed (group D) mice. To further evaluate the role of NKT cells in this model, mice in group E were tolerized following NKT depletion. To determine the effect of NKT depletion in a tolerized environment, tolerized mice in group F were NKT depleted following tolerance induction. Peripheral and intrahepatic NK1.1+ and CD4+/CD8+ T cells were determined in all groups. Colitis was assessed by standard clinical and histologic scores. Serum cytokines levels were measured by ELISA. RESULTS: Oral tolerance induction led to a marked alleviation of colitis as manifested by a significant improvement of the clinical, macroscopic, and microscopic scores of colitis (group A vs. group B). NK1.1+ depletion without tolerance induction had a favorable effect on colitis (C). Depletion of NKT LAL prevented the ability to induce tolerance (group D). However, induction of tolerance following NK1.1+ depletion, and NK1.1+ depletion following tolerance induction led to a marked improvement of colitis (groups E and F). Tolerance induction led to a significant increase in NKT LAL numbers. The peripheral CD4+/CD8+ ratio increased up to 3-fold in tolerized vs. non-tolerized mice. A similar increase was observed in NKT-depleted healthy mice in groups C, E, and F (P < 0.005). In contrast, NK1.1+ depletion in the presence of antigen in the bowel led to a reverse effect with a significant decrease in the peripheral CD4+/CD8+ ratio. An opposite effect was observed in the intrahepatic CD4+/CD8+. The peripheral/intrahepatic CD4+/CD8+ ratio increased significantly in tolerized and in healthy mice (A, D, E, F, P < 0.005). In contrast, NK1.1+ depleted fed mice in group C manifested a marked decrease in the peripheral/intrahepatic CD4+/CD8+ ratio. Induction of tolerance led to a marked increase in the IL-10/interferon gamma (IFNgamma) and IL-4/IFNgamma ratios. CONCLUSIONS: In the experimental colitis model, the liver is an important site for CD8+ accumulation during tolerance induction in a process that is independent of NK1.1+ cells. NK1.1+ cells play a dual role in the pro/anti-inflammatory balance. In the presence of antigen, these lymphocytes may be accountable for keeping an anti-inflammatory lymphocyte balance. However, in the absence of antigen, they may induce a pro-inflammatory shift.

Animals↗
PubMed2006

Mouse pregnancy-specific glycoproteins: tissue-specific expression and evidence of association with maternal vasculature.

The pregnancy-specific glycoproteins (Psg) are secreted hormones encoded by multiple genes in rodents and primates, and are thought to act as immune modulators. The only Psg receptor identified is CD9, through which Psg17 induces cytokine production from macrophages cultured in vitro. We examined temporal and spatial aspects of Psg and CD9 expression during mouse pregnancy to determine whether their expression patterns support a role in immune modulation. Using in situ hybridisation, immunohistochemistry and RT-PCR we found Psg expression in trophoblast giant cells and in the spongiotrophoblast. Psg22 is the predominant Psg family member expressed in giant cells. Detectable Psg is associated predominantly with endothelial cells lining vascular channels in the decidua, rather than with maternal immune cell markers. CD9 expression exhibited partial overlap with Psg, but without exclusive co-localisation. CD9 was observed in decidual cells surrounding early implantation sites, and in the endometrium. However, embryo transfer of wild-type embryos to CD9-deficient females indicates that maternal CD9 is not essential for successful pregnancy.

Animals↗
PubMed1995

Bifunctional antibody retargeting in vivo-activated T lymphocytes: simplifying clinical application.

For antitumor x anti-CD3 bifunctional antibody (BFA) therapy to be clinically relevant in solid tumors, activated lymphocytes must be present within tumors. Toward that end, three uniquely different in vivo activation approaches were investigated in a p97 human antigen expressing syngeneic murine melanoma model. beta-Glucan (200 micrograms), staphylococcal enterotoxin B (SEB) (50 micrograms), and F(ab')2 BFA (10 micrograms) were tested for their ability to activate lymphocytes, neutralize pulmonary metastases, and treat established tumors. Systemic activation, measured as the ability of splenocytes to lyse tumor cells in vitro in the presence of BFA, was enhanced by the in vivo administration of SEB but not by beta-glucan or F(ab')2 BFA. Despite lacking a systemic effect, F(ab')2 BFA increased both direct and BFA-mediated cytotoxicity in fresh tumor infiltrating lymphocytes. beta-Glucan did not increase systemic or intratumor T cell activation. However, it significantly enhanced the ability of splenocytes to lyse NK-sensitive YAC-1 cells. When tested in a pulmonary metastases model, all three forms of immune modulation combined with F(ab')2 BFA significantly reduced the number of metastases. BFA were more effective at tumor neutralization when combined with SEB compared with adoptively transferred, in vitro-activated splenocytes. These studies demonstrate that immune modulators when combined with F(ab')2 BFA can provide effective antitumor therapy. Several clinical obstacles may be overcome by the application of these reagents.

Animals↗
PubMed1989

Bioaccumulation of metals from a nickel smelter waste in P and F1 generations of exposed animals. II. Modulation of immune processes.

A group of female Chinchilla rabbits was exposed through inhalation to the metal aerosol derived from dumped waste of a nickel smelter. The experiments were carried out in a field exposure station. Increased levels of tissue immune complexes were found in the myocardium and lungs of P females, whereas F1 rabbits (exposed both prenatally and 6 weeks postnatally) from the same group of P females had significantly elevated serum circulating immune complexes as compared to controls. In P rabbits, nonspecific serum tumoricidal activity was increased by 8.2%, while in F1 animals the increase was by 14%. Transplantation immunity was examined in a group of inbred Lewis rats following the transplantation of a skin allograft from the ear of inbred Berlin-Druckrey rats. The mean time of allograft survival in animals following i.v. administration metal dust suspension 2 days prior to transplantation, was prolonged as compared to controls. On day 22 after allograft transplantation, lactate dehydrogenase activity was found to be reduced in peripheral lymphocytes, and the liver and spleen weight proved to be diminished. These findings suggest a modulating effect of the metal dust from a nickel smelter regarding nonspecific serum tumoricidal activity and transplantation immunity as well as immune complex formation.

Air Pollutants↗