Search

Nickel (Ni) in ambient air may vary regionally with contributions from both natural processes and anthropogenic activities. Exposure to Ni compounds in ambient air above a certain level is associated with acute adverse effects, such as upper respiratory tract irritation, pneumonitis, and chronic adverse effects, such as respiratory cancer. Inhalation reference exposure standards are enacted in different jurisdictions to minimize exposures to ambient Ni above levels that can elicit adverse effects. This paper reports a guideline-/GLP-compliant study designed for setting inhalation exposure standards to protect from immunological effects associated with acute exposure to Ni. Female CD-1 mice were exposed via whole-body inhalation to aerosolized nickel chloride hexahydrate for 24-hr at nominal (vs. mean analyzed) concentrations of 20 (16), 50 (44) and 100 (81) µg Ni/m3. Host T-cell antibody immunological responses to intravenously-injected sheep red blood cells were then measured ex vivo in an Antibody-Forming Cell (AFC) assay. Exposure to the Ni substance significantly decreased spleen cell levels by 33%, but this was within biological variability for outbred mice. No concurrent decreases in spleen, thymus, or body weights were noted. No immunosuppression was observed with the Ni substance in the context of Total Spleen Activity [IgM AFC/spleen (× 103)] and Specific Activity [IgM AFC/spleen cells (× 106)]. Significant concentration-independent increases in Total Spleen Activity and Specific Activity seen with the nickel chloride hexahydrate were normal and within biological variability for outbred mice. In contrast, cyclophosphamide (positive control) significantly decreased spleen cell numbers, spleen and thymus weights, and abolished Specific Activity and Total Spleen Activity. Based on results here, an NOAEC of 81 µg Ni/m3 for immunosuppressive effects from inhaled nickel chloride hexahydrate was identified. It is hoped this value can be used to derive a reference standard for human exposure to ambient Ni. [ABSTRACT FROM AUTHOR]

The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of studies and endpoints. While the functional assessment of CD8+ cytotoxic T-lymphocytes (CTL) is well-characterized in the clinic, the lack of a robust macaque CTL functional assay has been an important hurdle in evaluating and accurately quantifying cell-mediated CD8+ T-cell effector responses in the nonclinical setting. This paper describes the development of an assay to measure CTL activity in peripheral blood mononuclear cells (PBMC) isolated from Cynomolgus macaques. A human EGFR/CD3 Bispecific T-cell Engager (BiTE®) was used to mount a robust CD8+ T-cell response in the presence of target-expressing cells. Upon target engagement, degranulation of CD107a and production of interferon (IFN)-γ both reliably indicated a robust functional response in CD8+ T-cells. The BiTE®-mediated stimulation method proved to be favorable when compared to other methods of stimulation in the absence of target cells. These studies demonstrated acceptable longitudinal variability of the functional assay and sensitivity to dexamethasone-mediated immunosuppression. Taken together, the results indicated an assay leveraging CD3-bispecific antibodies and target-expressing cells can provide a robust approach to the in vitro or ex vivo assessment of CTL function in Cynomolgus macaques. Because the impairment of CTL activity by immunomodulators is recognized to be an important contributor to decreased antiviral defense and increased carcinogenicity risk, we believe that this novel assay to be a valuable addition to the immunotoxicology assessment of therapeutic drug candidates. [ABSTRACT FROM AUTHOR]

The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of studies and endpoints. While the functional assessment of CD8+ cytotoxic T-lymphocytes (CTL) is well-characterized in the clinic, the lack of a robust macaque CTL functional assay has been an important hurdle in evaluating and accurately quantifying cell-mediated CD8+ T-cell effector responses in the nonclinical setting. This paper describes the development of an assay to measure CTL activity in peripheral blood mononuclear cells (PBMC) isolated from Cynomolgus macaques. A human EGFR/CD3 Bispecific T-cell Engager (BiTE®) was used to mount a robust CD8+ T-cell response in the presence of target-expressing cells. Upon target engagement, degranulation of CD107a and production of interferon (IFN)-γ both reliably indicated a robust functional response in CD8+ T-cells. The BiTE®-mediated stimulation method proved to be favorable when compared to other methods of stimulation in the absence of target cells. These studies demonstrated acceptable longitudinal variability of the functional assay and sensitivity to dexamethasone-mediated immunosuppression. Taken together, the results indicated an assay leveraging CD3-bispecific antibodies and target-expressing cells can provide a robust approach to the in vitro or ex vivo assessment of CTL function in Cynomolgus macaques. Because the impairment of CTL activity by immunomodulators is recognized to be an important contributor to decreased antiviral defense and increased carcinogenicity risk, we believe that this novel assay to be a valuable addition to the immunotoxicology assessment of therapeutic drug candidates. [ABSTRACT FROM AUTHOR]

The present paper represents a comprehensive up-to-date review of β -glucans, their chemical and biological properties, and their role in immunological reactions. β -D-Glucans belong to a group of physiologically active compounds called biological response modifiers and represent highly conserved structural components of cell walls in yeast, fungi, or seaweed. Despite almost 150 years of research, the exact mechanisms of their action remain unclear. The present review starts with the history of glucans. Next, attention is focused on sources and structure, comparing the effects of physicochemical properties, and sources on biological effects. As glucans belong to natural products useful in preventing various diseases, they have been highly sought after throughout human history. Based on extensive recent research, this paper explains the various mechanisms of effects and the ways glucans mediate their effects on defense reactions against infections. Despite the fact that predominately pharmacological effects of glucans are positive, their unfavorable and potentially toxic side effects were not overlooked. In addition, attention was focused on the future research, possible alternatives such as synthetic oligosaccharides, and on clinical applications. [ABSTRACT FROM AUTHOR]

Research on the biological effects of vanadium in humans has shown that acute poisoning in workers can manifest itself in a number of symptoms. There are no reports in humans about reproductive and developmental effects induced by vanadium compounds in humans; however, some studies with rats and mice indicate that vanadium can cross the placental barrier and accumulate in fetal membranes rather than the fetus itself. In this case, probably most consequences of administration of vanadium to pregnant females like reabsorptions, fetal death and reduction in size can be the result of maternal toxicity. Concerning genetic and related effects in humans exposed to different vanadium compounds, data are controversial. Data on genotoxic effects in workers exposed to vanadium indicate that they can have an increased risk to develop cancer, and DNA instability can give rise to an onset of genetic syndromes, fetal malformations, and cancer. This paper presents materials presented at the 8th International Symposium on Vanadium Chemistry, Biological Chemistry, and Toxicology in a session titled 'Relationship between occupational and environmental exposure to vanadium compounds and the reprotoxic and genotoxic effects'. [ABSTRACT FROM AUTHOR]

Vanadium (V) has a variety of applications that make it suitable for use in ceramic production and decoration, production of pigments for a variety of products, an accelerator for drying paint, production of aniline black dye, and as a mordant in coloring textiles. Taking advantage of its hardness, resilience, ability to form alloys, and its resistance to corrosion, V is also used in the production of tools, steel, machinery, and surgical implants. V is employed in producing photographic developers, batteries, and semi-conductors, and in catalyst-based recycling processes. As technologies have evolved, the use of V has increased in jet aircraft and space technology, as well as in manufacture of ultraviolet filter glass to prevent radiation injury. Due to these myriad uses, the potential for occupational exposure to V is ever-evident. Similarly, there is an increased risk for environmental contamination by V agents themselves or as components of by-products released into the environment. For example, the use of V in sulfuric acid production results in the release of soot and/or fly ash rich in vanadium pentoxide. Petroleum refinery, smelting, welding, and cutting of V-rich steel alloy, the cleaning and repair of oil-fired boilers, and catalysis of chemical productions are other sources of increased airborne V-bearing particles in local/distant environments. Exposure of non-workers to V is an increasing health concern. Studies have demonstrated associations between exposure to airborne V-bearing particles (as part of air pollution) and increased risks of a variety of pathologies like hypertension, dysrhythmia, systemic inflammation, hyper-coagulation, cancers, and bronchial hyper-reactivity. This paper will provide a review of the history of V usage in occupational settings, documented exposure levels, environmental levels of V associated with pollution, epidemiologic data relating V exposure(s) to adverse health outcomes, and governmental responses to protect both workers and non-workers from exposure to this metal. [ABSTRACT FROM AUTHOR]

Vanadium (V) is a transition metal found in air adsorbed onto suspended particles. As a result, urban populations are often exposed to this element as a constituent of particulate matter (PM). One aspect of the myriad toxicities that might arise from these exposures is altered immune responses. Previous reports from the laboratory reported modifications in splenic architecture - with germinal center hyperplasia and a suppressed humoral immune response - in mice that had been exposed to vanadium agents via inhalation. This paper reports a decrease in the presence of the CD11c surface marker on mouse thymic dendritic cells (DC) as a result of host exposure to vanadium (here, in the form of vanadium pentoxide; V2O5) over a period of 4 weeks. All results were obtained using immunohistochemistry and flow cytometry. It is surmised that this decrease might induce a dysfunction, including possible negative selection of T-cells, which could increase the presence of autoreactive clones in the exposed host. Such an outcome could, in turn, increase the risk for development of autoimmune reactions in different organs specifically, and of autoimmune diseases in general in these V-exposed hosts. [ABSTRACT FROM AUTHOR]

Clinical activity of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4) monoclonal antibodies (mAb) has changed the approaches for the treatment of cancer in terms of patterns of response, duration of response, and adverse event profiles. In fact, antibodies that block the interaction of CTLA-4 with its ligands B7.1 and B7.2 can enhance immune responses, including anti-tumor immunity. Two recent studies using ipilimumab (an anti-CTLA-4 mAb) demonstrated improvements in overall survival in the treatment of advanced melanoma. These studies utilized two different schedules of treatment in different patient categories (first and second line of treatment). However, the results were quite similar despite the different dosage used and the combination with dacarbazine in the first line treatment. Ongoing clinical studies will establish the efficacy of ipilimumab as monotherapy or in combination with other drugs for the treatment of metastatic melanoma and a variety of other cancers. Other antibodies, such as CD137 agonists and PD-1 antagonists, are currently in various stages of pre-clinical and clinical development. Agonist antibodies directed against CD137 (4-1BB) on the surface of antigen-primed T-lymphocytes increase tumor immunity that is curative against some transplantable murine tumors. Programmed death-1 (PD1) is a surface molecule delivering inhibitory signals important to maintain T-cell functional silence against their cognate antigens. Interference with PD1 or its ligand PD-L1 (B7-H1) increases anti-tumor immunity. As a result, human mAbs anti-PD1 and anti-PD-L1 are under clinical development. This paper reviews recent studies in the treatment of advanced melanoma with these types of monoclonal antibodies. Ipilimumab can be considered a cornerstone of a new era in melanoma treatment. However, the aim is to optimize the therapy with anti-CTLA-4 antibodies to define the best schedule for next combination regimens (other immunomodulatory antibodies, BRAF/MEK inhibitors, vaccines, etc.) that represent the natural evolution of future melanoma therapy. [ABSTRACT FROM AUTHOR]

The intestinal environment is considered to play an important role both in colorectal tumor development and in the evolution and modulation of mucosal immunity. Studies in animals reared in germ-free (GF, without any intestinal microflora) versus conventional (CV, with regular microflora in bowel) conditions can aid in clarifying the influence of bacteria on carcinogenesis and anti-cancer immune responses in situ. The lower incidence of colon cancers and better immunological parameters in GF animals versus CV ones after chemically-induced carcinogenesis raises questions about specific characteristics of the immunological networks in each respective condition. Different levels of tolerance/regulatory mechanisms in the GF versus CV animals may influence the development of immune responses not only at the level of mucosal, but also at the systemic, immunity. We hypothesize that GF animals can better recognize and respond to evolving neoplasias in the bowel as a consequence of their less-tolerogenic immunity (i.e., due to their more limited exposure to antigens to become tolerated against at the intestinal level). In this paper, we review the role of bacteria in modulating gut environment and mucosal immunity, their importance in cancer development, and aspects of immune regulation (both at local and systemic level) that can be modified by bacterial microflora. Lastly, the use of GF animals in comparison with conventionally-raised animals is proposed as a suitable and potent model for understanding the inflammatory network and its effect on cancer immunity especially during colorectal cancer development. [ABSTRACT FROM AUTHOR]

The number of anti-inflammatory and immunomodulatory drugs being developed in the pharmaceutical industry has increased considerably in the past decade. This increase in research and development has been paralleled by questions from both regulatory agencies and industry on how best to assess decreased host resistance to infections or adverse immunostimulation caused by immunomodulatory agents such as anti-cytokine antibodies (e.g., the tumor necrosis factor-α inhibitors), anti-adhesion molecule antibodies (e.g., anti-α-4 integrin inhibitors) and immunostimulatory molecules (e.g., anti-CD28 antibodies). Although several methods have been developed for nonclinical assessment of immunotoxicity, highly publicized adverse events have brought to light significant gaps in the application of nonclinical immunotoxicity testing in assessing potential risk in humans. Confounding this problem is inconsistent application of immunotoxicology methods for risk assessment within the scientific community, limited understanding of appropriate immunotoxicity testing strategy for immunomodulators and inconsistent testing requests by regulatory agencies. To address these concerns, The Immunotoxicology Technical Committee (ITC) of the International Life Science Institute (ILSI) Health and Environmental Sciences Institute (HESI) organized a workshop on Immunomodulators and Clinical Immunotoxicology in May 2007. The Workshop was convened to identify key gaps in nonclinical and clinical immunotoxicity testing of anti-inflammatory and immunomodulatory agents and to begin to develop consistent approaches for immunotoxicity testing and risk assessment. This paper summarizes the outcome of the HESI ITC Immunomodulators and Clinical Immunotoxicology Workshop. Topics not discussed at the Workshop were outside the scope of this report. Although more work is needed to develop consistent approaches for immunotoxicity assessment of immunomodulators, this Workshop provided the foundation for future discussion. [ABSTRACT FROM AUTHOR]

The four most common immunodeficiencies in pediatric patients are transient hypogamma-globulinemia of infancy, IgG subclass deficiency, impaired polysaccharide responsiveness (partial antibody deficiency) and selective IgA deficiency. Most of these patients have normal cellular immune systems, phagocyte function and complement levels. All four illnesses are characterized by recurrent bacterial respiratory infections such as purulent rhinitis, sinusitis, otitis and bronchitis. Except for some IgA-deficient patients, the molecular basis for these illnesses is not known, and indeed each syndrome is heterogeneous, with multiple causes, including genetic factors, drug/environmental toxicant exposure, and/or prenatal physiological events. This paper describes the clinical and laboratory features, postulated causes, current management and prognosis. Only a few of these cases require the use of intravenous IgG (IVIG) and the outlook for long life is excellent. [ABSTRACT FROM AUTHOR]

The Center for Environmental Health Sciences (CEHS) Conference, entitled “Directions and Needs in Asbestos Research: New Insights,” was held at the University of Montana in Missoula. Researchers, physicians, health care workers, and federal agency representatives from around the country met for a cross-disciplinary exploration of many issues related to asbestos research. Topics included community and psychosocial issues in biomedical research, asbestos exposure assessment, assessment and mechanisms of asbestos related diseases, and new research directions. This meeting report is a summary of the conference presentations, and of the topics identified for future research directions. This conference was a follow-up to one hosted by the CEHS in June 2002, and continued to take advantage of opportunities to work with a unique population in Libby MT, where significant asbestos exposures have occurred due to the mining of asbestos-contaminated vermiculite. The goals of this conference were to bring together experts from diverse fields to identify progress made since the last conference and to develop new research avenues that would allow us to address the research needs in emerging asbestos-exposed populations. Participants indicated that these objectives were met, and expressed enthusiasm for follow-up conferences to maintain the dialog that has been established regarding directions and needs in asbestos research. Selected papers from the conference are presented here. [ABSTRACT FROM AUTHOR]

The therapeutic uses of immunostimulatory agents are generally in the treatments of infections or cancer. The traditional example of vaccination is one form of immunostimulation used in the prevention of pathogenic infections or cancer (e.g., human papillomavirus vaccine). Recombinant cytokines are increasingly used to stimulate immune system function. For example, interferon-α (IFNα) and interleukin (IL)-2 have been used to treat chronic hepatitis C virus infection and metastatic melanoma, respectively. In contrast, monoclonal antibodies are used to target malignant cells for elimination via antibody-dependent cytotoxicity mechanisms or apoptosis, including the anti-CD20 monoclonal antibody rituximab and the anti-CD56 monoclonal antibody alemtuzumab used in the treatment of B-cell malignancies, and the anti-erb2 receptor antibody trastuzumab used in the treatment of breast cancer. Finally, immunostimulation may develop via modulation of pathways involved in immune system regulation. For example, the anti-CD28 monoclonal antibody TGN1412 was developed as an agonist of regulatory T-cells for treatment of T-cell-mediated chronic inflammatory diseases or leukemias. A panel was convened to discuss potential toxicities associated with immunostimulation. At the Immunotoxicology IV meeting in 2006, a panel, moderated by Dr. Robert House (Dynport Vaccine Co., Frederick, MD), included Drs. Gary Burleson (Burleson Research Technologies, Inc., Raleigh, NC), Kenneth Hastings (US FDA, Center for Drug Evaluation and Research [CDER], Rockville, MD), Barbara Mounho (Amgen, Thousand Oaks, CA), Rafael Ponce (ZymoGenetics, Inc., Seattle, WA), Mark Wing (Huntington Life Sciences, Cambridgeshire, United Kingdom), Lauren Black (Navigators Consulting, Sparks, NV) and Anne Pilaro (US FDA, CDER, Rockville, MD). This paper reviews the major identified toxicities associated with immunostimulation, including the acute phase response, cell and tissue abnormalities/injury, cytokine release/cytokine storm, tumor lysis syndrome, vascular leak, and autoimmunity that were discussed by this panel. [ABSTRACT FROM AUTHOR]

Increased expectations from a number of regulatory agencies, e.g., Environmental Protection Agency (EPA), Food and Drug Administration (FDA), European Medicines Agency (EMEA), and the Ministry of Health, Labour and Welfare (MHLW) of Japan, call for the evaluation of potential adverse effects on the immune system. As recently summarized in the ICH S8 guideline, the T-cell-dependent antibody response (TDAR) has been identified in a regulatory context as a main functional test of immunotoxicity. While the characterization of immunotoxic potential is pertinent to both the chemical and pharmaceutical industries, the use of immunotoxicology data for hazard identification and/or risk assessment in each case is different. Therefore, multiple approaches to immunotoxicity testing have evolved. The assays that evaluate TDAR function include both well-established tests, e.g., anti-sheep red blood cell plaque-forming cell (PFC) assay, and newer models, e.g., anti-keyhole limpet hemocyanin (KLH) antibody ELISA. These tests vary in the study design, antigen application and analytical methods. However, they all evaluate the same endpoint - a competent immune (e.g., antibody) response to an antigen. Numerous issues have been identified in the application of TDAR tests, including high animal to animal variability; differences in antigen source and potency; a lack of established "normal range" of the immune response and uncertainty about the degree of inhibition of the TDAR to be considered toxicologically important. As such, the need for a forum to discuss these issues was recognized by the immunotoxicology community, and was addressed at the 2006 Society of Toxicology (SOT) Workshop. A series of papers will summarize that forum with the ultimate objectives being to build a consensus among immunotoxicologists on the implications of these factors on using TDAR results in hazard identification and/or risk assessment, and to establish a criteria to classify compounds as immunotoxicants. [ABSTRACT FROM AUTHOR]

Immunogenicity is an important factor that manufacturers must consider as they develop new protein therapeutics. It is important to understand the immunogenicity of new proteins both at the preclinical phase and in the clinical phase of development. This paper provides an overview of the issues that manufacturers should consider including some of the potential reasons that some proteins induce an immune response, a discussion regarding current methodology used to understand immunogenicity, and some examples of marketed protein therapeutics with immunogenicity issues. Given the increasing scrutiny from regulatory agencies around the way immunogenicity is assessed by manufacturers, the strategy of detecting and characterizing antibodies that are formed against protein therapeutics is becoming an important topic. Screening assays are typically performed first on all serum samples collected in the course of a trial to detect the presence of antibodies that can bind to the protein therapeutic. There are several platforms in use: radioimmune precipitation assays (RIP), enzyme linked immunosorbent assays (ELISA), electrochemiluminescent assays (ECL), and biosensor-based assays. Each has its advantages and disadvantages, and needs to be evaluated to identify the optimal platform for a specific therapeutic protein. Once antibodies are identified, a confirmatory assay is performed to verify and characterize the antibodies. A biological assay should be used next to test if these antibodies are capable of neutralizing the biological effect of the drug. Any sample that is positive for neutralizing antibodies, indicates that the antibody is probably having an impact on the patient's ability to derive full benefit from the therapeutic protein, and may be critical for patient safety. [ABSTRACT FROM AUTHOR]