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Immune system plays a key role in maintaining health, the adverse effect on the structure or function of the immune system consider as Immunotoxicity. Immunotoxic responses ranged from direct toxicity of the pharmaceutical component to indirect toxicities for immune system. In vitro methods standardization and validated have replaced or reduced some in vivo test and developing in vitro test able to predict compound's effects in vivo. Exposure to various chemicals associated with toxicity of the immune system which include environmental contaminants, chemicals in the occupational environment, and direct/ indirect food additives, accumulating evidence indicates that this system can be the target for immunotoxic effects caused by a variety of chemicals. Immunosuppression or enhancement can be associated with two distinct groups one is drugs intended and the other is drugs not intended which affect on immune functions.
Immunotoxicity refers to any, as a result of immune system dysfunction. Adverse effect may not necessarily to be appeared by change in an immune function or level of immunological mediator, but rather as immunostimulation.Various adverse effects may result in laboratory animals with immunotoxic potential. Generally, regulatory effects Caution must be exercised in such cases, because a non-specific enhancement of the immune response that might be interpreted as a beneficial effect may result in suppression of specific immunity against a particular infection (Guidance for industry and FDA reviewers, 1999). Immunotoxicology is a rapidly advancing field and new methods are constantly being developed and evaluated. Methods like genomics, proteomics, transgenic animals will become available to determine useful endpoints for drug safety assessment, such adverse effects as systemic hypersensitivity, autoimmunity, and photoallergy (Adkinson et al., 2002; Moser et al., 2001).
Immunotoxic responses can range from direct toxicity of the pharmaceutical to a component of the immune system to indirect toxicities, such as those thought to be involved in hypersensitivity responses. The importance of immunomodulation of the drugs for some pharmaceuticals with the clinical use of immunosuppressive therapeutics such as cytotoxic oncolytics and drugs used to prevent organ transplant rejection (Dean et al., 1979; Van Loveren H and Vos, 1989).
Effects to be considered adverse or immunotoxic if it impairs humoral (the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage) or cellular immunity needed by the host to defend itself against infectious or neoplastic disease (immunosuppression: effects on the immune system that result in decreased immune function) or it causes unnecessary tissue damage (autoimmunity, hypersensitivity, or chronic inflammation). This definition incorporates the concept of the immune system is in a complex balance which includes interactions with other systems such as nervous and endocrine system, that may affected or be utilize by the same biological mediators like neuropeptide and steroid hormones.
Vitro and vivo methods
Deferent institute are developing in vitro test able to predict compound's effects in vivo. In vitro methods standardization and validated have replaced or reduced some in vivo test (Genshow et al., 2002). Because those in vivo studies are very expensive, require a high number and raise important ethical concern. For this reason the European policy is promoting alternative methods to use of laboratory animals, in order to reduce and whenever possible replace animals employed for scientific studies and costs (Balls et al., 1995). For example enzyme linked immunosorbent assay (ELISA) techniques and the enzyme linked immunospot (ELISPOT) used to conduct for immune function studies which can quantitative antibody response and numbers of antibody producing cells, respectively (Holsapple, 1995; Johnson et al., 2000). Methods for test have been developed by using T-cell dependent immunogens (Exon and Talcott, 1995; Tryphonas et al., 2001).
Factors causing immuonotoxicity
Exposure to various chemicals such as polychlorinated biphenyls, chlorinated dibenzo-p-dioxins, pesticides, and heavy metals has been associated with toxicity of the immune system in animals; these include environmental contaminants, chemicals in the occupational environment, and direct and indirect food additives. Gardner et al. (2010) was studied the differential of immunotoxic effects of inorganic and organic mercury species in vitro. Recent work has indicated that the immunotoxic effects of mercury compounds may be significant contributors to human disease as well as mechanistically relevant to other target organ toxicities. This information on the immunotoxicity of Hg compounds is relatively limited at this time. The results showed that both organic and inorganic species of Hg can affect the human immune system, but that they may exert different effects on immune function. For one reason, most in vitro and in vivo studies have used Hg at relatively high concentrations compared to human exposure data in order to study the effects of Hg on the immune system (Pollard et al., 2005; Silbergeld et al., 2005).
The assessment of immunotoxicity is similar to the assessment of risk with toxicities in other organ systems which should include statistical and biological significance of changes; severity of the effects, relationship with dose and exposure, safety factor above the expected clinical dose, treatment duration, number of species, changes that may occur secondarily to other factors such as stress, possible cellular targets and mechanism of action, doses which produce these changes in relation to doses which produce other toxicities and reversibility of effects (EMEA, 2006). Development of immunotoxicity should be assessed in some cases. If a drug has been shown to have immunosuppressive potential in adult animal studies, the determination of potential developmental immunosuppression should be incorporated into reproductive toxicology study (ICH, 1994). Immunosuppression or enhancement can be associated with two distinct groups; one is drugs intended to modulate immune function for therapeutic purposes like prevention of organ transplant rejection, where adverse immunosuppression can be considered exaggerated pharmacodynamics (the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect), and the other is drugs not intended to affect immune function but cause immunotoxicity due to necrosis for example or apoptosis of immune cells or interaction with cellular receptors shared by both target tissues and non-target immune system cells ( EMEA 2006).
Indicators for determination of clinical and anatomical pathology indicative of immunosuppression like maternal drug exposure and its effects on lymphoid system histology and hematology in first generation offspring. Although methods have been proposed for assessing functional parameters of immunosuppression in neonatal animals (Ladics et al., 2000), no recommendation is made concerning appropriate studies to determine the effects on fetal and perinatal drug exposure on immune functions. If a drug used for prevention of perinatal transmission of HIV infection for instance, it should be included in the study of reproductive toxicology for determination of immunosuppressive potential. Drugs which belong to a known class can cause immunosuppression, the consideration should be given to conducting appropriate studies to determine potential effects on immune function. The general method is experimental determination of drug effect on immune response to a T-cell dependent immunogen (dependent on T-cell antibody response) the most widely accepted when immune function studies should be conducted. The useful identifying immunosuppressant chemicals is by using antisheep red blood cell (SRBC) primary IgM antibody response assay which usually referred to plaque assay; that extensively evaluated by the National Toxicology Program (Luster et al., 1988,1993). Plaque assay modifications are available can be used to determine the effects of drug on both IgM and secondary IgG immune responses to SRBC. There are several modifications for plaque assay can be used to determine the effects of drug on immune response to T-cell independent immunogen (Holsapple, 1995).