Biologic Markers in Immunotoxicology (1992) / Chapter Skim
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6 Animal Models for Use in Detecting Immunotoxic Potential and Determining Mechanisms of Action
6 Animal Models for Use in Detecting Immunotoxic Potential and Determining Mechanisms of Action
Pages 83-98
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From page 83... ...
Specific approaches and methods are outlined and discussed As &cussed ~ Chapter 3, immunogeninty of a xenobiotic substance In experimental animal models should provide a flag to indicate the potential of the xenobiotic to produce a hypersensitivity response in humans. Although every effort should be made to assess the impact of environmental exposure on the human immune system in human populations, experimental animals are We best surrogates for detecting harms xenon biotic substances and for determining their me~an~m of action.
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From page 84... ...
Although the mouse Is not used routinely in initial toxicologic evaluations, except In the determination of carcinogenic potential, the mouse immune system is well ~aractenzed, and most of the necessary reagents for ~mmunotomaty testing are specific for the mouse. Because the rat Is the animal used most often In Anal toxicologic evaluations of chenucals, most of the pharmacokinetic and toxicologic data available are for this species.
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From page 85... ...
Host-r~ance models Iistena mono~genes Streptococcus pneumonias or pyogerzes flues ~ B16;~10 melanoma tumor PYB6 tumor Mechanistic studies Interieuki'~-2 receptor oppression Ia rector expression Transfe~nn receptor expression Mac 1 and Mac 2 receptor expression F4/&0 receptor expression mENA for pytokines Complement components Anubo~y~ependent cell-mediated c~eotomc~ty Respiratory burst (macrophages, porno Ah onu clear leuko At es) Antigen presentation (Vos, 1977~.
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From page 86... ...
grams should include a complete blood-cell count; enumeration of the number of white blood cells; and a differential count of t}te lymphocytes, polymorphonuclearneutrophils, basophils, eosinophils, and monocles. The lymphoid organs that should be embed are the thymus, spleen, lymph nodes, and bone marrow.
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From page 87... ...
Cellular Immunity A cellular immune response results in the conducted. The generation of a primary generation of effecter cells that phago~ humoral immune response requires the or lyse invading antigens.
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From page 88... ...
Changes in T-cel1 responses to m~togen and cell-mediated immune responses, such as a delayed hypersensitiv~n,r response, also are correlated with ADORERS IN IMMUNOTO~COLOGY alterations ~ the ability of the mouse to eliminate Listena monocytogenes, herpes simplex virus, PYB6, and Plasmodiumyee11i. Nonspecific Immunity The immune system responds to and eliminates antigens before the generation of a specific immune response through nonspecif~c mechamcms.
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From page 89... ...
~^= Id Implied sew lo ~~e ==pe~c =-lemen1 pa_. ^~o~ ~ an 1~b ~ boon Bawd ~ m~^u ~ r^ce _.
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From page 90... ...
Several pulmonary June functions are important ~ ceD-mediated immures ag;m~;t viral disease and are proposed for use In AT IN IMMUN'OTOXlCOLOaY evaluating immunocompetence: interferon production alveolar macrophage function, natural-killer-cell activity, and (ytoto~c-Tlymphocyte (CI'L3 activity (Burieson, 1987, and persona]
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From page 91... ...
The cells responsible for long-term maintenance of antibody levels ~ the lung coma be ~portant In preventing recurrent pulmonary infections. The cells responsible for Iong-term antibody production are at risk of damage caused by inhaled pollutants.
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From page 92... ...
, could prove a valuable asset In assessing immune dysfunction. Other properties of the macros phage, such as respiratory burst, antigen presentation, monotone secretion, and acA~KERS INIMMUNOTO~COLOGY tivity, ~tostasis, c~oto~nci~, protease activity, and size heterogeneity, require additional investigation to assess their ability to reflect modulation by xenobiotics (Nathan, 1987~.
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From page 93... ...
However, high doses of allylating agents can injure pl~potential stem cells that might not be regenerated In animals, He immune responses could be intact when the ammals are challenged, but, if the stem cells are again insulted by acln~mi~tration of antimetabolites, a more severe and prolonged depressed response will occur. The reversibiIity of the effect on the immune system Is important information for hazard evaluation.
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From page 94... ...
(1985~. ~ the cell-mediated in1mlmity assays, no dose-related decreases were seen in either sew Humoral immune status was assessed by measuring quaniitation of spleen IBM antibody-forming cells (APCs3, hemagglutination titers to sheep erythropytes (SRBCs)
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From page 95... ...
Thus, the results give the best predicdon of the potential actions of a xenobiotic sum stance on the immune system. ~ contrast, the major source of ~mmunocompetent cells available for detestation of human immune status Is peripheral blood.
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From page 96... ...
Studies have shown that admini~tration of doses of malathion that inhibit acetylcholinesterase suppresses the humoral immune response to antigen (Casale et al., 19833. However, recent studies showed that administration of noncholinerg~c doses of malathion enhanced the immune response to antigen (Rodgers et al., 1986)
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From page 97... ...
RECOMMENDATIONS The Subcommittee on Tmmunoto~cology recombs ends that studies on the toasty of xenobiotic substances to human immune function include the generation of primary cellular and hum oral immune responses to an antigen, such as keyhole limpet hemopyanm. Inclusion of this assay ~ studies of alterations In immune responsiveness to xenob~otics should vastly enhance their usefulness.
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From page 98... ...
In vitro immunologic assays that can be used for rapid detection of potential ~mmunosuppressive agents need to be developed to detente cellular and subcellular sites of action. There needs to be investigation of the relationships between specific chemically induced immunosuppression and quantitative and qualitative changes In host resistance to microorganisms, parasites, and neoplastic diseases.
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