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The immune system evolved to discriminate self from nonself. Multicellular organisms were faced with the problem of destroying infectious invaders (microbes) or dysregulated self (tumors) while leaving normal cells intact. These organisms responded by developing a robust array of receptor-mediated sensing and effector mechanisms broadly described as innate and adaptive. Innate, or natural, immunity is primitive, does not require priming, and is of relatively low affinity, but is broadly reactive. Adaptive, or learned, immunity is antigen specific, depends on antigen exposure or priming, and can be of very high affinity. The two arms of immunity work closely together, with the innate immune system being most active early in an immune response and adaptive immunity becoming progressively dominant over time. The major effectors of innate immunity are complement, granulocytes, monocytes/macrophages, natural killer cells, mast cells, and basophils. The major effectors of adaptive immunity are B and T lymphocytes. B lymphocytes make antibodies; T lymphocytes function as helper, cytolytic, and regulatory (suppressor) cells. These cells are important in the normal immune response to infection and tumors but also mediate transplant rejection and auto-immunity. Immunoglobulins (antibodies) on the B-lymphocyte surface are receptors for a large variety of specific structural conformations. In contrast, T lymphocytes recognize antigens as peptide fragments in the context of self major histocompatibility complex (MHC) antigens (called human leukocyte antigens [HLAs] in humans) on the surface of antigen-presenting cells, such as dendritic cells, macrophages, and other cell types expressing MHC class I (HLA-A, -B, and -C) and class II antigens (HLA-DR, -DP, and -DQ) in humans. Once activated by specific antigen recognition via their respective clonally restricted cell-surface receptors, both B and T lymphocytes are triggered to differentiate and divide, leading to release of soluble mediators (cytokines, lymphokines) that perform as effectors and regulators of the immune response.
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The impact of the immune system in human disease is enormous. Developing vaccines against emerging infectious agents such as human immunodeficiency virus (HIV) and Ebola virus is among the most critical challenges facing the research community. Immune system–mediated diseases are significant medical problems. Immunological diseases are growing at epidemic proportions that require aggressive and innovative approaches to develop new treatments. These diseases include a broad spectrum of auto-immune diseases, such as rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus, and multiple sclerosis (MS); solid tumors and hematological malignancies; infectious diseases; asthma; and various allergic conditions. Furthermore, one of the great therapeutic opportunities for the treatment of many disorders is organ transplantation. However, immune system–mediated graft rejection remains the single greatest barrier to widespread use of this technology. An improved understanding of the immune system has led to the development of new therapies to treat immune system–mediated diseases.
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This chapter briefly reviews drugs used to modulate the immune response in three ways: immunosuppression, tolerance, and immunostimulation. Four major classes of immunosuppressive drugs are discussed: glucocorticoids (Chapter 42), calcineurin inhibitors, anti-proliferative and antimetabolic agents (...