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Chapter 55: Immunopharmacology

INTRODUCTION

The immune system is essential for protection against pathogens. However, when dysregulated, its powerful destructive mechanisms do more harm than good. Examples include hypersensitivity reactions, autoimmune disorders, and rejection of transplanted tissues. Drugs that suppress immune mechanisms play an important role in treating these conditions. Increasingly, monoclonal antibodies targeting proteins with key roles in immune responses are being developed as immunosuppressive agents. In some situations, drugs that potentiate the immune response provide benefit. A growing number of other conditions now rely on monoclonal antibodies as therapeutics (cancer, cardiovascular conditions, HIV, etc). A small subset of these newer drugs has been withdrawn from the market based on emerging toxicities.

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IMMUNE MECHANISMS

A. Overview

Using the concerted actions of complement components, phagocytic cells, and natural killer (NK) cells, the innate immune system initiates the defense against pathogens and antigenic insult. If the innate response is inadequate, the adaptive immune response is mobilized. This culminates in activation of T lymphocytes, the effectors of cell-mediated immunity, and production of antibodies by activated B lymphocytes, the effectors of humoral immunity. The subsets of lymphocytes that mediate different parts of the immune response can be identified by specific cell surface components or clusters of differentiation (CDs). For example, helper T (TH) cells bear the CD4 protein complex, whereas cytotoxic T lymphocytes express the CD8 protein complex.

B. Antigen Recognition and Processing

This critical inaugural step in the adaptive immune response involves antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B lymphocytes, which process antigens into small peptides recognized by T-cell receptors (TCRs) on the surface of CD4 TH cells (Figure 55–1). The most important antigen-presenting cell surface molecules are the major histocompatibility complex (MHC) classes I and II proteins, recognized by CD8 and CD4 T cells, respectively. The activation of TH cells by the class II MHC-peptide complex requires participation of costimulatory and adhesion molecules in addition to activation of T-cell receptors.

FIGURE 55–1

Scheme of cell-mediated and humoral immune responses. An immune response is initiated by internalization and processing of antigen by an antigen-presenting cell such as a macrophage. The class II MHC-peptide complex is recognized by the T-cell receptor (TCR) on T-helper (TH) lymphocytes, resulting in T-cell activation. Activated TH cells secrete cytokines such as IL-2, which cause proliferation and activation of TH1 and TH2 cells. TH1 cells produce IFN-γ and TNF-β, which activate macrophages and NK cells. A humoral response is triggered when B lymphocytes bind antigen via their surface immunoglobulins. They are then induced by TH2-derived cytokines (eg, IL-4, IL-5) to proliferate and differentiate into memory cells and antibody-secreting plasma cells. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 14th ed. McGraw-Hill, 2018: Fig. 55–3.)

An illustration shows the detailed steps in cell-mediated and humoral immunity.
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