Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches

Abstract

Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross reactivity with environmental allergens. Avoidance of the offending allergenic drug may impact disease management, quality of life, and life expectancy. Precision medicine provides new tools for the understanding and management of hypersensitivity reactions (HSRs), as well as a personalized treatment approach for IgE (Immunoglobuline E) and non-IgE mediated HSRs with drug desensitization (DS). DS induces a temporary hyporesponsive state by incremental escalation of sub-optimal doses of the offending drug. In vitro models have shown evidence that IgE desensitization is an antigen-specific process which blocks calcium flux, impacts antigen/IgE/FcεRI complex internalization and prevents the acute and late phase reactions as well as mast cell mediator release. Through a "bench to bedside" approach, in vitro desensitization models help elucidate the molecular pathways involved in DS, providing new insights to improved desensitization protocols for all patients. The aim of this review is to summarize up to date information on the drug HSRs, the IgE mediated mechanisms of desensitization, and their clinical applications.

Keywords: IgE; desensitization; desensitization models; drug hypersensitivity; high affinity IgE Fcε receptor I; mast cells; precision medicine.

Figure 1

Phenotypes and Endotypes in drug allergy. The new classification of DHRs is based on phenotypes, endotypes and biomarkers. Phenotypes include immediate and delayed reactions; the clinical presentations of each phenotype are mediated by different immunological mechanisms which are defined by endotypes. Biomarkers are used to identify the Endotypes (dash line box). Adapted from Muraro, Antonella, et al. “Precision Medicine in Allergic Disease–Food Allergy, Drug Allergy, and Anaphylaxis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.” Allergy (2017) [1]. BAT, basophil activation test; mAb, monoclonal antibody; α-Gal, galactose-alpha-1,3-galactose; NSAID, nonsteroidal anti-inflammatory; AERD, Aspirin Exacerbated Respiratory Disease; AECD, Aspirin Exacerbated Cutaneous Disease; HHV 6, human herpesvirus 6; HHV 7, human herpesvirus 7; EBV, Epstein Barr Virus; DRESS, Drug reaction with Eosinophilia and Systemic Symptoms; AGEP, Acute Generalized Exanthematous Pustulesis; SJS-TEN, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Figure 2

Schematic diagram represent of mast cells β-hexosaminidase in relation to time interval between doses and antigen doses during desensitization.

Figure 3

Mast cell IgE/Antigen desensitization inhibits the pre-formed mediators release, lipid mediators and cytokine production, and calcium flux and is antigen specific. 1. Pre-formed mediators release: (a) β-hexosaminidase release: MCs desensitized to DNP-HAS and OVA showed a 78% and 71% reduction of beta-hexosaminidase release, respectively compared to activated MCs with same allergen; (b) Pre-formed TNF-(white bars) and de novo synthesized TNF-(black bars) have a 62% and 75% reduction after desensitization, respectively compared with activation. 2. Lipid mediators production: (c) Arachidonic metabolites represent by Cysteinyl leukotriene C4 (LTC4), leukotriene B4 (LTB4), and 12(s)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT) were detected in MC supernatant after activation but not in control or desensitized MCs. 3. Cytokines production: (d) During DS, IL-6 production is 75% less than during activation. 4. calcium flux: (e) Calcium flux is impaired in OVA desensitized MCs after being triggered with activating dose of OVA but the influx is restored by activating with DNP-HAS non-desensitizing antigen (red line). Adapted from Sancho-Serra, et al., 2011 [53] with permission from John Wiley and Sons.

Figure 4

Simplified model comparing the outcomes of activated and rapidly desensitized mast cells. Resting mast cells (1) sensitizes with antigen-specific IgE bound to their high affinity IgE recepors (FcεRI) on cell surface (2) A: following the crosslinking of IgE/FcεRI receptors with an optimal dose of antigen leads to calcium flux (3–4), degranulation with release of the preformed mediators (5), early de novo synthesis of lipid mediators (6), and late cytokines/chemokines production(7). B: following administrating of suboptimal 11 doses to complete the same optimal dose as in A (activation) (3); leads to membrane rearrangements of receptors which impairs Ag/IgE/FcεRI complexes internalization and prevents all the hallmarks of MCs activation (red cross) such as calcium flux, degranulation, lipid mediators, and cytokine production.

Figure 5

Conclusions.