Granulysin-Based Lymphocyte Activation Test for Evaluating Drug Causality in Antiepileptics-Induced Severe Cutaneous Adverse Reactions

Chu, Mu-Tzu; Wang, Chuang‐Wei; Chang, Wen Han; Chen, Chun‐Bing; Chung, Wen Hung; Hung, Shuen‐Iu

doi:10.1016/j.jid.2020.11.027

Cited by 13 publications

(9 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, our in vitro co-culture assays with TCR transfectants further validated the pathogenic role of immunodominant TCR clonotype (i.e., TRAV12-3/TRBV28 pair and specific CDR3 region) in DDS-DIHS patients, and the CTLs expressing this TCR clonotype were demonstrated to produce high levels of inflammatory cytokines and cytotoxins in DDS- and HLA-B*13:01-dependent manner. Similarly, recent studies found shared TCR clonotypes in the blister cells [ 58 ] and in vitro expanded T cells [ 59 ] from PBMCs of carbamazepine-induced SJS/TEN patients. Apart from susceptible HLA alleles, the specific TCR clonotypes were deficient for drug metabolism/clearance that has also been linked to SCARs [ 15 ].…”

Section: Discussionmentioning

confidence: 72%

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Jiang

Wang

et al. 2022

J Biomed Sci

Self Cite

View full text Add to dashboard Cite

Background Severe cutaneous adverse drug reactions (SCARs) are a group of serious clinical conditions caused by immune reaction to certain drugs. The allelic variance of human leukocyte antigens of HLA-B*13:01 has been strongly associated with hypersensitivities induced by dapsone (DDS). T-cell receptor mediated activation of cytotoxic T lymphocytes (CTLs) has also been suggested to play an essential role in pathogenesis of SCARs. However, HLA-B*13:01-DDS-TCR immune synapse that plays role in drug-induced hypersensitivity syndrome (DIHS) associated T cells activation remains uncharacterized. Methods To investigate the molecular mechanisms for HLA-B*13:01 in the pathogenesis of Dapsone-induced drug hypersensitivity (DDS-DIHS), we performed crystallization and expanded drug-specific CTLs to analyze the pathological role of DDS-DIHS. Results Results showed the crystal structure of HLA-B*13:01-beta-2-microglobulin (β2M) complex at 1.5 Å resolution and performed mutation assays demonstrating that I118 or I119, and R121 of HLA-B*13:01 were the key residues that mediate the binding of DDS. Subsequent single-cell TCR and RNA sequencing indicated that TCRs composed of paired TRAV12-3/TRBV28 clonotype with shared CDR3 region specifically recognize HLA-B*13:01-DDS complex to trigger inflammatory cytokines associated with DDS-DIHS. Conclusion Our study identified the novel p-i-HLA/TCR as the model of interaction between HLA-B*13:01, DDS and the clonotype-specific TCR in DDS-DIHS. Graphical Abstract

show abstract

Section: Discussionmentioning

confidence: 72%

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Jiang

Wang

et al. 2022

J Biomed Sci

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our previous study demonstrated that HLA-B*13:01, HLA-B*15:02, HLA-B*38:02 and HLA-B*39:01 are strongly associated with sulfamethoxazole/trimethoprim-induced severe cutaneous adverse reactions in Asians, including SJS, TEN, and drug reactions with eosinophilia and systemic symptoms (DRESS) ( 14 ). In addition, granulysin-based lymphocyte activation tests represent in vitro cytotoxic T-lymphocyte memory response to culprit drugs and are useful to confirm drug causality and drug-induced severe cutaneous adverse reactions ( 13 ). A low score calculated by ALDEN score of drug causality in SJS/TEN and the Naranjo algorithm ( 13 , 18 ), a negative lymphocyte activation test for sulfamethoxazole/trimethoprim, and an absence of HLA-B risk genotypes helped to exclude the possibility of sulfamethoxazole/trimethoprim-induced SJS/TEN.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, granulysin-based lymphocyte activation tests represent in vitro cytotoxic T-lymphocyte memory response to culprit drugs and are useful to confirm drug causality and drug-induced severe cutaneous adverse reactions ( 13 ). A low score calculated by ALDEN score of drug causality in SJS/TEN and the Naranjo algorithm ( 13 , 18 ), a negative lymphocyte activation test for sulfamethoxazole/trimethoprim, and an absence of HLA-B risk genotypes helped to exclude the possibility of sulfamethoxazole/trimethoprim-induced SJS/TEN. Last, the donor lymphocyte macrochimerism (19% of HLA originated from the donor) in recipient peripheral blood further confirmed the diagnosis of aGVHD.…”

Section: Discussionmentioning

confidence: 99%

“…The histopathological features showed mild lichenoid dermatitis and was consistent with GVHD. The granulysin- and granzyme B-based lymphocyte activation tests ( 13 ) both showed negative response to sulfamethoxazole/trimethoprim. Human leukocyte antigen (HLA) genotyping revealed an absence of HLA-B*13:01, HLA-B*15:02 , HLA-B*38:02 and HLA-B*39:01 , which were identified as a significant genomic indicator for drug-induced severe cutaneous adverse reactions, including SJS/TEN ( 14 ).…”

Section: Case Descriptionmentioning

confidence: 99%

See 1 more Smart Citation

Diagnostic and therapeutic dilemma in Stevens–Johnson syndrome-like acute graft-versus-host disease after liver transplantation: A case report

et al. 2022

Self Cite

View full text Add to dashboard Cite

BackgroundAcute graft-versus-host disease (aGVHD) is a severe and fatal complication after orthotopic liver transplantation (OLT). Clinical manifestations of severe aGVHD can resemble drug-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and there are also various medications, such as antibiotics and immunosuppressants, used after transplantation, causing a diagnostic dilemma. Furthermore, there have been no standardized diagnostic and therapeutic strategies for OLT-aGVHD due to its rarity.Case summaryA 52-year-old man presented with generalized maculopapular eruptions, fever, and pancytopenia 1 month after OLT and 4 days after taking sulfamethoxazole/trimethoprim. After assessment of the scoring criteria for drug causality of drug allergy, histopathological findings of skin biopsy, lymphocyte activation test of the potential offending drug, and microchimerism study, the diagnosis was in favor of aGVHD mimicking SJS/TEN. Considering severe sepsis, the anti-tumor necrosis factor alpha (TNF-α) agent, etanercept, was used to replace tacrolimus and corticosteroid. Skin lesions resolved gradually after anti-TNF-α biologics rescue; tacrolimus and corticosteroid therapy were re-administrated after controlling sepsis. Pancytopenia recovered and the patient was discharged in a stable condition.ConclusionWe demonstrated a diagnostic strategy for OLT-aGVHD. Targeting therapy with anti-TNF-α blockade and a temporary withdrawal of traditional immunosuppressants may be among effective and safe therapeutic options of OLT-aGVHD for those with severe sepsis.

show abstract

“…В тесте активации лимфоцитов in vitro описано выявление цитотоксических Т-клеток памяти со специфическим к лекарству Т-клеточным рецептором у пациентов с тяжелыми побочными реакциями, затрагивающими кожу по механизму замедленной гиперчувствительности, на ароматические противоэпилептические препараты [10]. Вероятно, выявленное в нашем исследовании выраженное увеличение в периферической крови Т-клеток эффекторной памяти CD45RA -CD3 + CD8 + CD294 + CD27 + CD28 + CCR7отражает возможность развития у пациентов в том числе и замедленных реакций гиперчувствительности IV типа.…”

Section: Discussionunclassified

CD3<sup>+</sup>CD294<sup>+</sup>T cells of the type 2 immune response: their role in allergic inflammation

Бычкова

2022

Med. immunol.

View full text Add to dashboard Cite

T lymphocytes type 2 immune response protect against helminths and toxins, and also contribute to the development of allergic inflammation. One of the most specific T cell surface markers T lymphocytes 2 is the CRTH2 molecule (CD294), which is an activating receptor for prostaglandin D2. The CD3+CD294+ population is negligible in the peripheral blood of healthy individuals; an increase occurs in patients with allergic diseases and an autoimmune nature of the response. The aim of the study was to study the quantitative and functional characteristics Т lymphocytes type 2 immune response in patients with rhinoconjunctival symptoms (n = 248) and drug hypersensitivity (n = 184). In 68 patients with an elevated and extremely high number of CD3+CD294+ cells, a detailed phenotype of this population was characterized by flow cytometry and the functional activity of the studied cell population in relation to the production of interleukin 4 and interferon γ was studied using enzyme immunoassay. The control group consisted of 34 volunteers. The relative number of CD3+CD294+ cells was significantly higher in the group of patients with drug hypersensitivity – 1.6% and rhinoconjunctival symptoms 1.2% compared to the control group – 1.0%. Elevated (1.6-3.6%) and extremely high (>3.6%) CD3+CD294+ cell number were significantly more frequently detected in patients with drug hypersensitivity. In both groups, an increase in the number of CD3+CD294+ cells were observed with severe damage to the skin. The phenotype of the population T lymphocytes type 2 CD45RA-CD3+CD294+CD2+CD5+CD7+CD27+CD28+CD57-CCR7- was determined, which corresponds to effector memory T lymphocytes. With a moderately increased relative amount of this population, T lymphocytes 2 were usually represented by T helpers 2. A pronounced increase in the population was observed due to T cytotoxic lymphocytes 2. Regardless of the predominance of the Т helper or Т cytotoxic 2 cells in patients revealed an increase in spontaneous production of interleukin 4 at a normal level of interferon. An increase in the peripheral blood T lymphocytes with CD294 expression contributes to the development, maintenance and exacerbation of allergic inflammation with the participation of IgEdependent and IgE-independent mechanisms. The CD3+CD294+ cell population should be determined as an additional parameter in assessing the presence of sensitization in the basophil activation test in patients with hypersensitivity reactions. The use of this laboratory biomarker to assess the dominant type of immune inflammation will make it possible to personalize the therapy of the examined patients. Identification of pronounced deviations of indicators from the average values of a population will influence the tactics of patient management.

show abstract

Granulysin-Based Lymphocyte Activation Test for Evaluating Drug Causality in Antiepileptics-Induced Severe Cutaneous Adverse Reactions

Cited by 13 publications

References 44 publications

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Diagnostic and therapeutic dilemma in Stevens–Johnson syndrome-like acute graft-versus-host disease after liver transplantation: A case report

CD3<sup>+</sup>CD294<sup>+</sup>T cells of the type 2 immune response: their role in allergic inflammation

Contact Info

Product

Resources

About