Identification of drug-specific public TCR driving severe cutaneous adverse reactions

Published on Aug 8, 2019in Nature Communications14.919
· DOI :10.1038/S41467-019-11396-2
Ren-You Pan6
Estimated H-index: 6
(Memorial Hospital of South Bend),
Mu-Tzu Chu3
Estimated H-index: 3
(NYMU: National Yang-Ming University)
+ 15 AuthorsShuen-Iu Hung5
Estimated H-index: 5
(NYMU: National Yang-Ming University)
Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.
Figures & Tables
📖 Papers frequently viewed together
#1Jianxiang Zhang (RUC: Renmin University of China)H-Index: 1
#2Lingyu Wang (Duke University)H-Index: 8
T-cell receptor–engineered T-cell therapy and chimeric antigen receptor T-cell therapy are 2 types of adoptive T-cell therapy that genetically modify natural T cells to treat cancers. Although chim...
#1Shih-Chi Su (Memorial Hospital of South Bend)H-Index: 31
#2Chun-Bing ChenH-Index: 14
Last. Wen-Hung ChungH-Index: 55
view all 22 authors...
: To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA-B*13:01, HLA-B*15:02, and HLA-B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificiti...
#1Pavlina Chuntova (UCSF: University of California, San Francisco)H-Index: 8
#2Kira Downey (UCSF: University of California, San Francisco)H-Index: 4
Last. Hideho Okada (UCSF: University of California, San Francisco)H-Index: 62
view all 5 authors...
Malignant gliomas carry a dismal prognosis. Conventional treatment using chemo- and radiotherapy has limited efficacy with adverse events. Therapy with genetically engineered T-cells, such as chimeric antigen receptor (CAR) T-cells, may represent a promising approach to improve patient outcomes owing to their potential ability to attack highly infiltrative tumors in a tumor-specific manner and possible persistence of the adaptive immune response. However, the unique anatomical features of the br...
#1Marco Cardone (CDER: Center for Drug Evaluation and Research)H-Index: 2
#2Karla Garcia (CDER: Center for Drug Evaluation and Research)H-Index: 1
Last. Michael A. NorcrossH-Index: 23
view all 15 authors...
Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show tha...
#1Wei-Ti Chen (Memorial Hospital of South Bend)H-Index: 5
#2Chuang Wei Wang (CGU: Chang Gung University)H-Index: 4
Last. Wen-Hung ChungH-Index: 55
view all 15 authors...
Dapsone-induced hypersensitivity reactions may cause severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). It has been reported that HLA-B*13:01 is strongly associated with dapsone-induced hypersensitivity reactions among leprosy patients. However, the phenotype specificity and detailed immune mechanism of HLA-B*13:01 remain unclear. We investigated the genetic predisposition, HLA-B*13:01 function, and cytotoxic T cells involved in the pathoge...
#1Chuang-Wei Wang (Memorial Hospital of South Bend)H-Index: 14
#2Lan-Yan YangH-Index: 16
Last. Wen-Hung ChungH-Index: 55
view all 19 authors...
BACKGROUND. Cytotoxic T lymphocyte–mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed ...
#1Chun-Bing ChenH-Index: 14
#2Riichiro Abe (Niigata University)H-Index: 43
Last. Wen-Hung ChungH-Index: 55
view all 7 authors...
Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic ...
#2Chuang Wei Wang (Memorial Hospital of South Bend)H-Index: 4
Background Proton pump inhibitors (PPIs) have been known to induce type I hypersensitivity reactions. However, severe delayed-type hypersensitivity reactions (DHR) induced by PPI, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), are rarely reported. We conducted a study of a large series of PPI-related DHR, followed up their tolerability to alternative anti-ulcer agents, and investigated the T-cell reactivity ...
#1Yong-Chen Lu (NIH: National Institutes of Health)H-Index: 21
#2Zhili Zheng (NIH: National Institutes of Health)H-Index: 40
Last. Steven A. Rosenberg (NIH: National Institutes of Health)H-Index: 244
view all 12 authors...
The adoptive transfer of neoantigen-reactive tumor-infiltrating lymphocytes (TILs) can result in tumor regression in patients with metastatic cancer. To improve the efficacy of adoptive T cell therapy targeting these tumor-specific mutations, we have proposed a new therapeutic strategy, which involves the genetic modification of autologous T cells with neoantigen-specific T cell receptors (TCRs) and the transfer of these modified T cells back to cancer patients. However, the current techniques t...
Cited By42
#2Adriana ArizaH-Index: 21
Last. María José TorresH-Index: 58
view all 7 authors...
The immunological mechanisms involved in drug hypersensitivity reactions (DHRs) are complex and, despite important advances, multiple aspects remain poorly understood. These not fully-known aspects are mainly related to the factors that drive towards either a tolerant or a hypersensitivity response, and specifically regarding the role of B and T cells. In this review, we focus on recent findings on this knowledge area within the last two years. We highlight new evidences of covalent and non-cova...
#1Takeshi Susukida (University of Toyama)H-Index: 6
#2Saki Kuwahara (Chiba University)H-Index: 1
Last. Kousei Ito (Chiba University)H-Index: 30
view all 6 authors...
Idiosyncratic drug toxicity (IDT) associated with specific human leukocyte antigen (HLA) allotype is a rare and unpredictable life-threatening adverse drug reaction for which prospective mechanistic studies in humans are difficult. Here, we show the importance of immune tolerance for IDT onset and determine whether it is susceptible to a common IDT, HLA-B*57:01-mediated abacavir (ABC)-induced hypersensitivity (AHS), using CD4+ T cell-depleted programmed death-1 receptor (PD-1)-deficient HLA-B*57...
#1Christina S. M. Wong (Li Ka Shing Faculty of Medicine, University of Hong Kong)
#2Desmond Y H Yap (Li Ka Shing Faculty of Medicine, University of Hong Kong)H-Index: 18
Last. Janette Kwok (QMUL: Queen Mary University of London)H-Index: 7
view all 8 authors...
BACKGROUND: HLA-B*15:11 is associated with carbamazepine (CBZ)-induced severe cutaneous adverse drug reactions (SCARs) in Japanese and some Asian populations, but such data remains relatively limited in Chinese. Routine HLA-B*15:02 screening is mandatory before CBZ commencement, however, SCARs related to CBZ were still observed in non-HLA*B-15:02 carriers. OBJECTIVE: We aimed to find out the prevalence of HLA-B*15:11 in Chinese patients and its associations with CBZ-induced SCARs. METHOD: We scr...
#1Pooja Deshpande (UWA: University of Western Australia)H-Index: 5
#2Rebecca J Hertzman (UWA: University of Western Australia)
Last. Elizabeth J. Phillips (UWA: University of Western Australia)H-Index: 64
view all 7 authors...
The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T-cell mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA-B*57:01, the 100% negative predictive value and low number needed to test to prevent a single...
#1Elisa Maria Schunkert (Brigham and Women's Hospital)
#2Pranali Shah (Brigham and Women's Hospital)H-Index: 5
Last. Sherrie J. Divito (Brigham and Women's Hospital)H-Index: 19
view all 0 authors...
Delayed-type drug hypersensitivity reactions (dtDHR) are immune-mediated reactions with skin and visceral manifestations ranging from mild to severe. Clinical care is negatively impacted by a limited understanding of disease pathogenesis. Though T cells are believed to orchestrate disease, the type of T cell and the location and mechanism of T cell activation remain unknown. Resident memory T cells (TRM) are a unique T cell population potentially well situated to act as key mediators in disease ...
#1Yuanyuan Zheng (Tongji University)H-Index: 21
#2Yan Li (Tongji University)H-Index: 2
Last. Yingqun Zhou (Tongji University)H-Index: 32
view all 11 authors...
Primary liver cancer (PLC) is a common malignancy with high morbidity and mortality. Poor prognosis and easy recurrence on PLC patients calls for optimizations of the current conventional treatments and the exploration of novel therapeutic strategies. For most malignancies, including PLC, immune cells play crucial roles in regulating tumor microenvironments and specifically recognizing tumor cells. Therefore, cellular based immunotherapy has its instinctive advantages in PLC therapy as a novel t...
#1Rebecca J. Hertzman (Murdoch University)H-Index: 1
#2Pooja Deshpande (Murdoch University)
Last. Elizabeth J. Phillips (Murdoch University)H-Index: 64
view all 4 authors...
PURPOSE OF REVIEW An update of the pharmacogenetic risk factors associated with T-cell-mediated delayed hypersensitivity reactions. RECENT FINDINGS Recent HLA associations relevant to our understanding of immunopathogenesis and clinical practice include HLA-B*13:01 with co-trimoxazole-induced SCAR, and HLA-A*32:01 with vancomycin-DRESS, for which an extended HLA class II haplotype is implicated in glycopeptide antibiotic cross-reactivity. Hypoactive variants of ERAP1, an enzyme-trimming peptide ...
#1Mu-Tzu Chu (NYMU: National Yang-Ming University)H-Index: 3
#2Chuang-Wei Wang (Core Laboratories)H-Index: 14
Last. Shuen-Iu Hung (NYMU: National Yang-Ming University)H-Index: 5
view all 6 authors...
Aromatic antiepileptic drugs (AEDs) are common causes of cutaneous adverse drug reactions, which range from morbilliform drug eruption to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens‒Johnson syndrome, and toxic epidermal necrolysis. Different in vitro methods for identifying the culprit drugs have been developed; however, it is particularly challenging for Stevens‒Johnson syndrome-toxic epidermal necrolysis. In this...
#1Paul J. Thomson (University of Liverpool)H-Index: 7
#2Laila Kafu (University of Liverpool)H-Index: 2
Last. Dean J. Naisbitt (University of Liverpool)H-Index: 60
view all 10 authors...
Background Atabecestat is an orally administered BACE inhibitor developed to treat Alzheimer's disease. Elevations in hepatic enzymes were detected in a number of in trial patients, which resulted in termination of the drug development programme. Immunohistochemical characterization of liver tissue from an index case of atabecestat-mediated liver injury revealed an infiltration of T-lymphocytes in areas of hepatocellular damage. This, coupled with the fact that liver injury had a delayed onset s...
Drug hypersensitivity reactions (DHR) are heterogeneous and unusual immune reactions with rather unique clinical presentations. Accumulating evidence indicates that certain non-covalent drug-protein interactions are able to elicit exclusively effector functions of antibody reactions or complete T cell reactions which contribute substantially to DHR. Here, we discuss three key interactions; a) mimicry: whereby soluble, non-covalent drug-protein complexes ("fake antigens") mimic covalent drug-prot...
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.