The Structure and Function Of the Immune System And Mechanisms of Immunotoxicity
T- Cell Reactions
Immune-system reactions that result in specific T-lymphocyte activation and response can cause T cells to act as autoimmune effector cells (Turk, 1980). Alternatively, some T-cell-dependent reactions might result in the formation of granulomas (Turk, 1980; Springer et al., 1987) (Table 2-1). Activated T cells produce and release lymphokines, biochemical factors that mediate T-cell reactions. Some lymphokines activate blood monocytes to cause their transformation to macrophages; others are chemotactic for monocytes and attract them into tissue sites. If the process is chronic (lasts for weeks or months), the attracted macrophages cluster and fuse to form giant cells in the tissue at the site of lymphocyte activation. Those cellular events produce a typical lesion called a granuloma. The
THE STRUCTURE AND FUNCTION OF THE IMMUNE SYSTEM AND MECHANISMS OF IMMUNOTOXICITY 29
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multinucleate giant cells (macrophages) are mixed with clusters of mononuclear cells (macrophages and lymphocytes). Granulomatous reactions are characteristic of chronic T-cell-dependent reactions (Table 2-1).
They are found in infectious diseases in which the antigen persists with continued T-cell activation.
Granulomatous reactions are common in tuberculosis and in fungal infections. They also can occur with exposure to particulate chemicals such as beryllium and talc.
Another T-cell-dependent tissue injury results from the binding of specific T-effector cells to a cell-bound antigen on target cells. Such effector cells are called killer T cells because they release chemicals that kill the target cell shortly after contact. Examples are found in a variety of viral infections, chemical contact sensitivity, and drug reactions. In chemical contact sensitivity, the chemical becomes adsorbed to a cell surface and becomes the target antigen for specific effector T cells that kill the cell linked to the chemical.
EFFECTS OF XENOBIOTICS ON THE IMMUNE SYSTEM
Some drugs and chemotherapeutic agents can suppress the immune system. These agents are used clinically to prevent rejection of transplanted organs and in the treatment of some autoimmune diseases. When the drugs are administered at doses that prevent organ rejection, patients are at increased risk of infection and neoplasia as a consequence of their reduced immune function. Other xenobiotics are suspected of causing immunosuppression in humans through environmental exposure, but definitive evidence is lacking.
Toxic agents might cause abnormalities in immune function at several points. These points are illustrated in Figure 2-3 superimposed on the model in Figure 2-2. There are four major sites at which toxic agents might affect immune function (Gibson et al., 1983; Luster et al., 1987). At point 1, a toxic material could lead to a specific immune response that produces tissue injury through
FIGURE 2-3 A model of the competent immune system depicting sites of potential effects on the major components by toxic factors.
THE STRUCTURE AND FUNCTION OF THE IMMUNE SYSTEM AND MECHANISMS OF IMMUNOTOXICITY 30
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any of the different types of immunologic injury (Twomey, 1982). At point 2, a toxic agent could alter the activity of specific lymphocytes. The result can be either a regulatory defect in the immune function, which could lead to excessive immune reactivity, or an autoimmune reaction (Twomey, 1982). A third point of potential toxic effect might be on lymphocyte proliferation or differentiation that could lead either to a defect or to an enhancement of specific reactivity. Finally, at point 4, immune reactivity could be excessive in widespread activation of other cells (macrophages, granulocytes, platelets, and mast cells), activation of potent plasma biochemical systems (complement, fibrinolytic, coagulation, and kinin), or secretion of biochemicals from stimulated lymphocytes.
Chemicals that suppress bone marrow function can affect the reserves of stem cells that are needed for cell replacement. Blood-cell lines are derived from pluripotent stem cells, which in adult humans are primarily in the bone marrow. Within the marrow microenvironment, these self-renewing cells mature into committed progenitor cells, which are in peripheral blood and tissues. The continued development of these cells is under the control of various growth factors, many of which originate in bone marrow stromal cells. Bone marrow stromal cells also provide a supporting matrix for development of hematopoietic cells. Various studies, including those on the use of long-term bone marrow cultures, have demonstrated the importance of the microenvironment in regulating myeloid and lymphoid development. Stem cells often appear to be sensitive targets for therapeutic and environmental toxicants, most likely because of their rapid proliferation. Myelotoxicity or bone marrow toxicity caused by xenobiotics or various drugs can result in profound immunosuppression due to loss of stem cells.
Xenobiotics can act as immunogens to stimulate the production of specific immunoglobulin as a part of an immune response. Specific immunoglobulins might be used as markers of exposure to specific xenobiotics.
Other biologic markers that could be applied to the human immune system are discussed in subsequent chapters. They are derived principally from or related to the varied biochemical and cellular factors discussed in the foregoing sections. They include the total and relative numbers of circulating lymphocytes and their subpopulations; the different classes of immunoglobulins (in addition to the specific antibodies already mentioned); lymphocyte proliferation stimulated by mitogens and specific antigens (xenobiotics); complement activation by specific xenobiotics; skin test response patterns to xenobiotics; in vitro lymphocyte and monocyte activation by xenobiotics, with measurement of lymphokine secretion; and other markers found by the techniques of cellular and molecular biology that can sensitively assess the structure, function, and complex interactions of the many components of the immune system. Animal models could prove useful in defining appropriate immune-system markers for xenobiotics in humans. The study and application of immune-system markers in humans to the assessment of toxic environmental exposures are now in the initial stages. Many questions require experimental and epidemiologic answers to ascertain the usefulness of particular markers. It is expected that this report will help stimulate the major research needed.
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