Hypersensitivity reactions to small molecule drugs

Abstract

Drug hypersensitivity reactions induced by small molecule drugs encompass a broad spectrum of adverse drug reactions with heterogeneous clinical presentations and mechanisms. These reactions are classified into allergic drug hypersensitivity reactions and non-allergic drug hypersensitivity reactions. At present, the hapten theory, pharmacological interaction with immune receptors (p-i) concept, altered peptide repertoire model, and altered T-cell receptor (TCR) repertoire model have been proposed to explain how small molecule drugs or their metabolites induce allergic drug hypersensitivity reactions. Meanwhile, direct activation of mast cells, provoking the complement system, stimulating or inhibiting inflammatory reaction-related enzymes, accumulating bradykinin, and/or triggering vascular hyperpermeability are considered as the main factors causing non-allergic drug hypersensitivity reactions. To date, many investigations have been performed to explore the underlying mechanisms involved in drug hypersensitivity reactions and to search for predictive and preventive methods in both clinical and non-clinical trials. However, validated methods for predicting and diagnosing hypersensitivity reactions to small molecule drugs and deeper insight into the relevant underlying mechanisms are still limited.

Keywords: allergic drug hypersensitivity reactions; drug hypersensitivity reactions; hypersensitivity evaluation for investigational new drugs or post-marketing drugs; non-allergic drug hypersensitivity reactions; screening hypersensitivity reactions in clinical practice; small molecule drugs.

Figure 1

Classification of ADHRs. (A) Type I ADHRs. Drugs stimulate the generation of drug-specific IgE, which binds to high-affinity IgE receptors on the surface of mast cells and basophils. The drugs then react with specific IgE–effector cell complexes and induce the release of histamine and other inflammatory mediators. (B) Type II ADHRs. Specific IgG or IgM antibody-coated cells encounter complement-dependent cytotoxicity to induce cell lysis. (C) Type III ADHRs. Deposition of drug–antibody complexes activates the complement system or other immune cells to induce inflammation and injury. (D) Type IVa ADHRs. Th1 cells mediate macrophage/monocyte activation. (E) Type IVb ADHRs. Th2 cells mediate eosinophil activation. (F) Type IVc ADHRs. Cytotoxic T cells act as effector cells to produce cytotoxic mediators and kill tissue cells. (G) Type IVd ADHRs. T cells mediate neutrophil activation. MC, mast cells; RBC, erythrocytes; WBC, leukocytes; PLT, platelets; ENDO, endothelial cells; MONO, monocytes; MAC, macrophages; EO, eosinophils; KC, keratinocytes; NEUT, neutrophils; APCs, antigen-presenting cells.

Figure 2

The mechanisms involved in allergic hypersensitivity reactions to small molecule drugs. (A) Hapten theory. (B) Altered peptide model of p-i HLA and allo-immune model of p-i HLA. (C) p-i TCR model. (D) Fake antigen model. (E) Drug-induced immune thrombocytopenia. APCs, antigen- presenting cells; HLA, human leukocyte antigen; TCR, T-cell receptor; MC, mast cells; PLT, platelets; GP, glycoprotein; CDR, complementary-determining region.

Figure 3

The mechanisms involved in non-allergic hypersensitivity reactions to small molecule drugs. (A) Direct activation of mast cells. (B) Activation of complement. (C) Inhibition of cyclooxygenases. (D) Elevation of bradykinin. (E) Activation of the RhoA/ROCK signaling pathway. ER, endoplasmic reticulum; MRGPRX2, Mas-related G protein-coupled receptor X2; PLCγ, phospholipase C gamma; IP3, inositol triphosphate; IP3R, inositol triphosphate receptor; PKC, protein kinase C; P38, p38(MAPK) pathway; MAC, membrane attack complex; 12-/15-/5-HETEs, 12-/15-/5-hydroxy eicosatetraenoic acids; 12-/15-/5-HPETE, 12-/15-/5-hydroperoxyeicosatetraenoic acid; LTA4/LTB4/LTC4/LTD4/LTE4, leukotriene A4/B4/C4/D4/E4; PGG2/PGI2/PGE2/PGE2a/PGD2, prostaglandin G2/I2/E2/E2a/D2; TXA2, thromboxane A2; BKR-2, bradykinin receptor type 2; JAK, Janus-activated kinase; STAT3, signal transducer and activator of transcription 3; DAG, diacylglycerol; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PLA2, phospholipase A2; PGs, prostaglandins; LTs, leukotrienes; GDP-Rho A, an inactive GDP-bound Ras homolog family member A; GTP-Rho A, an active GTP-bound Ras homolog family member A; ROCK, Rho-associated kinase; MLC, myosin light chain; p-MLC, phospho-myosin light chain; MLCP, myosin light chain phosphatase.