New Approaches to Investigate Drug-Induced Hypersensitivity

Ogese, Monday O.; Ahmed, Shaheda; Alferivic, Ana; Betts, Catherine J.; Dickinson, Anne; Faulkner, Lee; French, Neil S.; Gibson, Andrew; Hirschfield, Gideon M.; Kammüller, Michael; Meng, Xiaoli; Martin, Stefan F.; Musette, Philippe; Norris, Alan; Pirmohamed, Munir; Park, B. Kevin; Purcell, Anthony W.; Spraggs, Colin F.; Whritenour, Jessica; Naisbitt, Dean J.

doi:10.1021/acs.chemrestox.6b00333

Cited by 19 publications

(22 citation statements)

References 184 publications

(304 reference statements)

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“…This study focused on BP as a drug model since it has been associated with heterogeneous clinical allergic reactions, and it is known to bind covalently to selective lysine residues on proteins . According to the hapten hypothesis, adducts formed inside and outside of the antigen‐presenting cells usually undergo protein processing to generate MHC‐binding peptides that are assumed to contain the drug modification . Moreover, our group has previously showed the pre‐existence of a naïve CD4+ T cell repertoire for BP .…”

Section: Discussionmentioning

confidence: 69%

Identification and characterization of a naïve CD8+ T cell repertoire for benzylpenicillin

Bechara

Maillère

Joseph

et al. 2019

Clin Experimental Allergy

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Background: Beta-lactams allergy is the most commonly reported drug allergy and constitutes an important health problem. We previously showed the pre-existence of a naïve CD4+ T cell repertoire for benzylpenicillin (BP) coupled to human serum albumin (HSA) but little is known about the naïve CD8+ T cell repertoire specific for BP.Objective: The purpose of this work was to identify naïve CD8+ T cells specific for BP and to explore mechanisms dictating their activation.Methods: Co-cultures were established with naïve CD8+ T cells and autologous dendritic cells (DCs) loaded with HSA-BP or free BP. T cells were restimulated once a week with autologous DCs loaded with HSA-BP or BP. The specific CD8+ T cell response was measured using an IFN-γ ELISpot assay.Results: When using free BP, we were able to detect a naïve CD8+ T cell repertoire for BP in the 6 out of 7 tested healthy donors. However, our results showed that HSA-BP was recognized by naïve CD8+ T cells in only one donor out of five tested healthy donors. Using free BP, we evidenced its binding to cellular proteins in DCs that was concentration dependent and was correlated with BP-specific CD8+ T cell activation. Moreover, the BP-specific CD8+ cell response was MHC class I-dependent and required intracellular processing and proteasome activity. Conclusion and clinical relevance:This work showed the existence of a naïve CD8+ T cell repertoire for BP when DCs were treated with free BP suggesting that patients could be immunized by haptenated peptides from cellular proteins generated in antigen-presenting cells.

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Section: Discussionmentioning

confidence: 69%

Identification and characterization of a naïve CD8+ T cell repertoire for benzylpenicillin

Bechara

Maillère

Joseph

et al. 2019

Clin Experimental Allergy

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“…The HLA-B * 57:01 and B * 57:03 alleles are protective against HIV disease progression, and appear to present identical Gag epitopes (Payne et al, 2014 ). HLA-B * 57:01, B * 57:02 , and B * 57:03 share more than 90% sequence homology and as such have peptide-binding repertoires which substantially overlap (Illing et al, 2012 ; Ogese et al, 2017 ). Although in ART naïve patients HLA-B * 57 ( B * 57:01 in Europe and US, B * 57:03 in black Africans) confers protective effect against HIV-1 disease progression to AIDS (Costello et al, 1999 ; Migueles et al, 2000 ; López-Larrea et al, 2005 ; Frater et al, 2007 ), it may exert contradictory effect on treatment outcome when the disease course is altered by ARV therapy (Dold et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

HLA-B*57 Allele Is Associated with Concomitant Anti-tuberculosis and Antiretroviral Drugs Induced Liver Toxicity in Ethiopians

et al. 2017

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Drug-induced liver injury (DILI) is a known adverse effect of both anti-tuberculosis (anti-TB) and antiretroviral (ARV) drugs. Recent studies highlight the implications of genetic predispositions to DILI. We performed a case-control study to identify Human Leukocyte Antigen-B (HLA-B) variant alleles associated with anti-TB and ARV co-treatment induced liver toxicity in Ethiopian TB and HIV co-infected patients. A total of 495 newly diagnosed TB and HIV co-infected patients were enrolled and received rifampicin based anti-TB and efavirenz based ARV therapy. Change in liver enzyme level from baseline was monitored 1st, 2nd, 4th, 8th, 12th, and 24th weeks after treatment initiation to identify patients who developed DILI (cases) and those who did not (treatment tolerants). Genomic DNA from 46 cases and 46 sex and age matched treatment tolerants were genotyped for HLA-B variant alleles using Olerup SSP®HLA-B DNA Typing Kits. The proportion of HLA-B*57 allele carriers in DILI cases (37.0%), particularly in those who developed cholestatic type of DILI (44.8%) was significantly higher compared with those who tolerated the treatment (2.2%). The HLA-B*57 allele frequency was significantly higher in cases (25%) than treatment tolerants (1.1%). In a multivariate logistic analysis, the proportion of patients carrying HLA-B*57 (P = 0.002) and HLA-B*14 (P = 0.014) alleles were significantly higher in DILI cases compared with treatment tolerants. HLA-B*57 was significantly associated with cholestatic (P = 0.001) and mixed (P = 0.017) types of liver toxicity, and mild-to-moderate severity (P = 0.001). Of all HLA-B*57 alleles detected, HLA-B*57:03 accounted 58.3% and HLA-B*57:02 accounted 41.7%. HLA-B*57:01 was not detected. The variant allele frequencies of HLA-B*57:03 (15.2 vs. 0%) and HLA-B*57:02 (9.8 vs. 1.1%) were significantly higher in the DILI cases than treatment tolerants (P < 0.03). We conclude that HLA-B*57 alleles (B*57:03 and B*57:02) confer susceptibility to the development of anti-TB and ARV drugs co-treatment induced liver toxicity, which is mainly of cholestatic type. The possible association of HLA-B*14 with anti-TB and ARV drugs co-treatment induced liver toxicity requires further investigations.

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“…Furthermore, the cross-talk between tissue and immune cells is important in determining the outcome of compound exposure. For example, hepatocytes treated with model hepatotoxins release signals that promote the secretion of polarizing cytokines from DC (Ogese et al 2017). Thus, new strategies need to be developed to enhance exposure of immune cells to relevant tissue-specific stress signaling and tissue-derived drug-protein adducts.…”

Section: Tissue Microenvironmentmentioning

confidence: 99%

The skin as a metabolic and immune-competent organ: Implications for drug-induced skin rash

Sharma

Saito

Chung³

et al. 2018

Journal of Immunotoxicology

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Current advances in the study of cutaneous adverse drug reactions can be attributed to the recent understanding that the skin is both a metabolically and immunologically competent organ. The ability of the skin to serve as a protective barrier with limited drug biotransformation ability, yet highly active immune function, has provided insights into its biological capability. While the immune response of the skin to drugs is vastly different from that of the liver due to evolutionary conditioning, it frequently occurs in response to various drug classes and manifests as a spectrum of hypersensitivity reactions. The skin is a common site of adverse and idiosyncratic drug reactions; drug-specific T-cells, as well as involvement of an innate immune response, appear to be key mechanistic drivers in such scenarios. Association of other factors such as human leukocyte antigen (HLA) polymorphisms may play a significant role for particular drugs. This review aims to integrate emerging findings into proposed mechanisms of drug metabolism and immunity in the skin that are likely responsible for rashes and other local allergic responses. These unique biological aspects of the skin, and their translation into implications for drug development and the use of animal models, will be discussed.

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New Approaches to Investigate Drug-Induced Hypersensitivity

Cited by 19 publications

References 184 publications

Identification and characterization of a naïve CD8+ T cell repertoire for benzylpenicillin

Identification and characterization of a naïve CD8+ T cell repertoire for benzylpenicillin

HLA-B*57 Allele Is Associated with Concomitant Anti-tuberculosis and Antiretroviral Drugs Induced Liver Toxicity in Ethiopians

The skin as a metabolic and immune-competent organ: Implications for drug-induced skin rash

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