Immune-mediated Mechanisms of ADRs

There are three major categories of ADRs related to the immune system: immunotoxicity, autoimmune reactions, and hypersensitivity or allergic reactions.1 Immunotoxicity may be the specific intent of therapy, e.g., when monoclonal antibodies target specific B cells. Alternatively, it may occur as an ADR to therapy when cytotoxic agents designed to kill malignant cells also damage normal cells in the bone marrow and lymphoid tissues. Immunotoxicity may also result in secondary ADRs, e.g., infections and oncogenesis.

Drugs can also initiate autoimmune reactions resulting in a person’s immune system attacking his/her own cells. For example, a drug may elicit an antibody response to Rh factors on red blood cells (RBCs) causing hemolytic anemia; or induce an antibody response to myeloperoxidase or DNA causing a lupus-like syndrome; or directly cause mast cell degranulation resulting in urticarial lesions; or cause blistering lesions of the skin and mucous membranes, e.g., erythema multiforme or Stevens-Johnson syndrome.

Hypersensitivity or allergic reactions reflect drug-related immunogenicity. Therapeutic peptides or proteins with molecular weights >600 daltons are recognized by the immune system as foreign substances and can directly trigger allergic reactions. Drugs with molecular weights <600 daltons are too small to act as direct immunogens; however, these drugs may act as haptens. Haptens bind covalently to large endogenous protein molecules and the hapten-protein complex triggers the allergic response.

The Gell-Coombs classification system proposes four mechanisms of hypersensitivity or allergic reactions: type I or immediate hypersensitivity reactions (anaphylaxis), type II or antibody-dependent cytotoxic reactions, type III or immune complex-mediated reactions (serum sickness), and type IV or delayed T cell-mediated reactions.1,3 An allergic response is predicated on sensitization, i.e., prior exposure to a drug. At highest risk are adults, women, patients with HIV infection, and those with history of allergy to related drugs.

Type I or immediate hypersensitivity reactions (anaphylaxis) are predicated on exposure to an allergen and antigen-specific antibody production dominated by immunoglobulin E (IgE) isotype.1,3 Upon re-exposure IgE antibodies bind to mast cells in mucosal and epithelial tissues (Figure 1). The simultaneous binding of an antigen to adjacent IgE molecules fixed to Fc receptors triggers degranulation of mast cells resulting in the production and release of histamine, leukotrienes, prostaglandins, and cytokines.

Figure 1. Type I or Immediate Hypersensitivity Reaction.

Illustration of Type I or immediate hypersensitivity reaction.

Type II or antibody-dependent cytotoxic reactions are predicated on exposure to an allergen and antigen-specific antibody production dominated by immunoglobulin G (IgG) or M (IgM) isotypes.1,3 Upon re-exposure the antigen binds to the surface of target cells (usually RBCs), the antigen-antibody complexes attract cytotoxic T cells, which release chemical mediators that cause target-cell lysis (Figure 2). Alternatively, antigen-antibody complexes attached to target-cells may activate complement-mediated target-cell lysis.

Figure 2. Type II or Antibody-dependent Hypersensitivity Reaction.

Illustration of Type II or antibody-dependent hypersensitivity reaction.

Type III or immune complex-mediated reactions (serum sickness) are predicated on exposure to an allergen and antigen-specific antibody production dominated by immunoglobulin G (IgG) or M (IgM) isotypes.1,3 Upon re-exposure soluble drug molecules form large insoluble antigen-antibody complexes that are deposited in target tissues (e.g., kidneys, joints and lungs) and initiate complement activation, neutrophil and platelet aggregation, and an intense inflammatory response (Figure 3).

Figure 3. Type III or Immune Complex-mediated Reaction.

Illustration of Type III or immune complex-mediated reaction.

Type IV or delayed T cell-mediated hypersensitivity reactions are predicated on exposure to haptens, which bind to endogenous macromolecules and form hapten-protein complexes.1,3 Langerhans cells phagocytize and process hapten-protein complexes, load them into major histocompatibility complexes, migrate to regional lymph nodes and present them to naïve T-lymphocyte. Upon re-exposure sensitized T cells in target tissues activate macrophages, which mediate direct cellular damage (Figure 4).

Figure 4. Delayed T Cell-mediated Hypersensitivity Reaction.

Illustration of delayed T cell-mediated hypersensitivity reaction.