Chapter 35: Immunosuppressants, Tolerogens, and Immunostimulants

INTRODUCTION

This chapter reviews the components of the immune response and drugs that modulate immunity in 3 ways: immunosuppression, tolerance, and immunostimulation. Four major classes of immunosuppressive drugs are discussed: glucocorticoids (see Chapter 42), calcineurin inhibitors, antiproliferative and antimetabolic agents (see Chapter 61), and antibodies. The chapter ends with a brief case study of immunotherapy for MS.

THE IMMUNE RESPONSE

The immune system evolved to discriminate self from nonself. Innate immunity (natural immunity) is primitive, does not require priming, and is of relatively low affinity, but is broadly reactive. Adaptive immunity (learned immunity) is antigen specific, depends on antigen exposure or priming, and can be of very high affinity. The 2 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 autoimmunity.

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 and class II antigens. Once activated by specific antigen recognition, 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.

IMMUNOSUPPRESSION

Immunosuppressive drugs are used to dampen the immune response in organ transplantation and autoimmune disease. In transplantation, the major classes of immunosuppressive drugs used today are:

• Glucocorticoids

• Calcineurin inhibitors

• Antiproliferative/antimetabolic agents

• Biologicals (antibodies)

Table 35–1 summarizes the sites of action of representative immunosuppressants on T-cell activation.