Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome

Ko, Tai‐Ming; Chung, Wen Hung; Chi, Chun‐Wei; Shih, Han-Yu; Chen, Jung Kuei; Lin, Chia Hsien; Chen, Yuan Tsong; Hung, Shuen Iu

doi:10.1016/j.jaci.2011.08.013

Cited by 237 publications

(228 citation statements)

References 40 publications

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“…ALP/OXPTCCs were generated by limiting dilution, as described elsewhere (22). The specificity of TCCs was assessed by increased CD107a expression on FACS, IFN-g ELISPOT assay, or [ 51 Cr]-release assay, as previously described (15,18,23).…”

Section: T Cell Line and T Cell Clone Generationmentioning

confidence: 99%

“…Unlike HLA-B*57:01 and flucloxacillin (16), all ALP/OXP-specific T cells were activated via the p-i mechanism, regardless of their HLA-B*58:01 status. Unlike HLA-B*57:01 and abacavir (19), the drug binding was labile, and unlike HLA-B*15:02 and carbamazepine (15), there was no shared TCR usage within reactive T cells. Moreover, OXP-specific T cells from HLA-B*58:01 + individuals were selectively restricted to this molecule, whereas ALP-specific T cells also were restricted to other unrelated HLA molecules for the drug recognition.…”

mentioning

confidence: 99%

“…certain TCR repertoires is also an important risk factor (15). Furthermore, our group (16) recently showed that flucloxacillinspecific T cells restricted to HLA-B*57:01 recognize the drug via the p-i mechanism and not as a haptenized peptide.…”

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confidence: 99%

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Oxypurinol Directly and Immediately Activates the Drug-Specific T Cells via the Preferential Use of HLA-B*58:01

Yun

Marcaida

Eriksson

et al. 2014

The Journal of Immunology

144

174

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Allopurinol (ALP) hypersensitivity is a major cause of severe cutaneous adverse reactions and is strongly associated with the HLA-B*58:01 allele. However, it can occur in the absence of this allele with identical clinical manifestations. The immune mechanism of ALP-induced severe cutaneous adverse reactions is poorly understood, and the T cell–reactivity pattern in patients with or without the HLA-B*58:01 allele is not known. To understand the interactions among the drug, HLA, and TCR, we generated T cell lines that react to ALP or its metabolite oxypurinol (OXP) from HLA-B*58:01+ and HLA-B*58:01− donors and assessed their reactivity. ALP/OXP-specific T cells reacted immediately to the addition of the drugs and bypassed intracellular Ag processing, which is consistent with the “pharmacological interaction with immune receptors” (p-i) concept. This direct activation occurred regardless of HLA-B*58:01 status. Although most OXP-specific T cells from HLA-B*58:01+ donors were restricted by the HLA-B*58:01 molecule for drug recognition, ALP-specific T cells also were restricted to other MHC class I molecules. This can be explained by in silico docking data that suggest that OXP binds to the peptide-binding groove of HLA-B*58:01 with higher affinity. The ensuing T cell responses elicited by ALP or OXP were not limited to particular TCR Vβ repertoires. We conclude that the drug-specific T cells are activated by OXP bound to HLA-B*58:01 through the p-i mechanism.

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Section: T Cell Line and T Cell Clone Generationmentioning

confidence: 99%

mentioning

confidence: 99%

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Oxypurinol Directly and Immediately Activates the Drug-Specific T Cells via the Preferential Use of HLA-B*58:01

Yun

Marcaida

Eriksson

et al. 2014

The Journal of Immunology

144

174

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“…Moreover, some HLA alleles are only associated with particular manifestations of a response and only in certain ethnic populations. More recently, T-cell receptor clonotypes have been reported to play a significant role in carbamazepine-associated severe cutaneous responses (Ko et al, 2011), but this has not yet been defined for other drugs. It is apparent that the mechanisms for hypersensitivity reactions are multi-factorial, and, while predisposing factors may be identifiable, it is difficult to identify all of the contributing factors that result in hypersensitivity reactions in every situation.…”

Section: Introductionmentioning

confidence: 99%

Development and partial validation of a mouse model for predicting drug hypersensitivity reactions

Whritenour

Cole

Zhu

et al. 2013

Journal of Immunotoxicology

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Animal models that can be used to predict the allergenic potential of drug candidates have not been adequately optimized, validated, or characterized. While initial validation data from an inter-laboratory study of the mouse lymph node proliferation assay (LNPA) appeared promising, no additional investigations in this model have been reported. The objectives of this study were to use positive and negative control drugs to further optimize and validate the LNPA utilizing a non-radioactive endpoint and determine the sensitivity, specificity, and predictivity of the model. Drugs associated with hypersensitivity reactions in the literature were chosen to test in the model in addition to drugs with few or no reports of hypersensitivity. Mice received a subcutaneous injection of drug or vehicle into the scruff of the neck once daily for a period of 3 days. On Day 6, draining lymph nodes were harvested, single cell suspensions prepared, and total cell numbers determined for each animal by flow cytometry. A stimulation index was calculated by dividing the mean total cell number for the drug-treated group by the mean total cell number for the vehicle-treated animals. Based on statistical analysis of the data, animals with a total cell number !2.5Â the mean of the vehicle group were classified as 'responders'. Based on data generated to date with 12 positive control and six negative control drugs, the model had a sensitivity of 75%, a specificity of 74%, and a relatively good predictive value (measured by the Receiver Operating Characteristic AUC of 0.80). The data here suggest that this model may be a useful tool for identifying drug candidates with the potential to produce allergic responses in the clinic. Future studies will investigate the mechanism(s) for the lymph node responses in order to develop additional endpoints that may increase the sensitivity and specificity of the model.

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“…For abacavir and carbamazepine, it has been possible to relate the genetic association to the mechanism of disease by characterizing drug-specific CD8þ T-cell responses in volunteers expressing HLA-B*57:01 and B*15:02, respectively. 6,7 The role of T cells in drug reactions targeting the liver is less well defined. In 1997, Maria and Victorino 8 described lymphocyte proliferative responses to drugs in over 50% of patients with drug-induced liver injury (DILI).…”

mentioning

confidence: 99%

Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury

et al. 2013

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Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome

Cited by 237 publications

References 40 publications

Oxypurinol Directly and Immediately Activates the Drug-Specific T Cells via the Preferential Use of HLA-B*58:01

Oxypurinol Directly and Immediately Activates the Drug-Specific T Cells via the Preferential Use of HLA-B*58:01

Development and partial validation of a mouse model for predicting drug hypersensitivity reactions

Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury

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