Immune dysregulation increases the incidence of delayed‐type drug hypersensitivity reactions

Abstract

Delayed-type, T cell-mediated, drug hypersensitivity reactions are a serious unwanted manifestation of drug exposure that develops in a small percentage of the human population. Drugs and drug metabolites are known to interact directly and indirectly (through irreversible protein binding and processing to the derived adducts) with HLA proteins that present the drug-peptide complex to T cells. Multiple forms of drug hypersensitivity are strongly linked to expression of a single HLA allele, and there is increasing evidence that drugs and peptides interact selectively with the protein encoded by the HLA allele. Despite this, many individuals expressing HLA risk alleles do not develop hypersensitivity when exposed to culprit drugs suggesting a nonlinear, multifactorial relationship in which HLA risk alleles are one factor. This has prompted a search for additional susceptibility factors. Herein, we argue that immune regulatory pathways are one key determinant of susceptibility. As expression and activity of these pathways are influenced by disease, environmental and patient factors, it is currently impossible to predict whether drug exposure will result in a health benefit, hypersensitivity or both. Thus, a concerted effort is required to investigate how immune dysregulation influences susceptibility towards drug hypersensitivity. K E Y W O R D Sdrug hypersensitivity, HLA, immune checkpoint inhibitors, regulation, T cells

Hypersensitivity reactions to IL-1 and IL-6 inhibitors are linked to common HLA-DRB1*15 alleles

“…Evidence suggests that underlying immune dysregulation greatly enhances the chance that a T cell response to an offending drug will escalate to clinical significance. 8 Consistent with this, we observed DRESS in systemic juvenile idiopathic arthritis (sJIA), a chronic inflammatory disease of childhood with unknown etiology. 9 We noted DRESS among sJIA patients who developed an unusual, non-infectious parenchymal diffuse lung disease (DLD) during immunosuppressive treatment with inhibitors of IL-1 (anakinra, canakinumab, rilonacept) or of IL-6 (tocilizumab).…”

“…The immune dysregulation in sJIA and KD likely underlies the failure to restrain this T cell response. 3 Our findings highlight the need for surveillance for DReSS to IL-1/IL-6 inhibitors, which is often missed, especially when it occurs during active systemic inflammatory disease. Importantly, DHR in sJIA may initiate or substantially contribute to DLD (Table S2).…”

“…Several molecular mechanisms for the modification of HLA into an immunogenic moiety have been identified or proposed. 8 A detailed picture of the pathogenesis of clinical DHR remains to be elucidated and may involve a complex interplay between viruses, HLA proteins, T cells, cytokine secretion and other genetic polymorphisms. 1,6,23…”

Számít-e a gyógyszer dózisa a túlérzékenységi reakciókban?

“…A gyógyszer okozta hiperszenzitivitási reakció kialakulásához nem mindig alapfeltétel a klasszikus dendritikus sejt általi antigénfeldolgozás és -prezentáció, valamint T-sejt-receptor-felismerés. Az immunpatogenezis-kaszkád elindításában jelenleg 3, kölcsönösen egymást nem kizáró modellt feltételeznek, ezek a hapten/prohapten (klasszikus útvonal, kovalens kötés), a p-i elmélet (nemkovalens kapcsolódás) és a megváltozott fehérjerepertoár elmélete (2. táblázat) [7][8][9][10]. A TEN -mint hiperszenzitivitási reakció -rizikója, illetve a már kialakult reakció súlyossága arányos a plazma-gyógyszerkoncentráció szintjével, ami alátámasztja a gyógyszermolekula és az immunreceptor ritka, nemkovalens interakciójának elméletét, hiszen a klasszikus prezentációs útvonalon (hapten/prohapten) beindított immunmechanizmusok nem dózisfüggőek [3].…”

The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity

“…Since the treatment of the DTH entity remains challenging, there is a need for physicians to look into the detailed interactions between immune cells and explore novel therapeutic targets (14)(15)(16)(17). Fortunately, current evidence has demonstrated that both the dysregulations of regulatory T cells (Tregs) and the dysfunction of certain co-signaling axes are associated with the development of cutaneous inflammatory disease (18,19). In this review, we summarize the established pathogenesis of clinically-relevant DTHs then focus on currently suggested concepts regarding how Tregs and various costimulatory and coinhibitory receptors regulate different components and cytokines in DTH in the hope of clarifying potential targets for future treatment.…”