Investigating Delayed-Onset Drug Hypersensitivity Reactions Prospectively

Delayed-type drug hypersensitivity reactions (dtDHR) are significant causes of morbidity and mortality, but the origin, phenotype and function of pathogenic T cells across the spectrum of severity are unknown. Research has been hampered by several barriers. We leveraged recent technical advancements to study skin-resident memory T cells (TRM) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), and skin-limited disease, morbilliform drug eruption (MDE). As part of the overarching study, we used single cell RNA sequencing (scRNA-seq) with CITE sequencing and TCR sequencing on prospectively collected skin and blood samples from patients with SJS/TEN and MDE patients. We compared this to healthy controls obtained from discarded skin from surgeries and discarded blood collars from a blood donation center. These data are included here in dbGaP database. The overarching study also performed bulk transcriptional profiling and microscopic analysis of clinical skin samples, as well as a mouse model of MDE (PMID: 39042477). Together, the data supported clonal expansion and recruitment of cytotoxic CD8+ T cells (identified using the mean normalized expression of NKG7, GNLY, GZMA, GZMB, and PRF1) from circulation into skin, along with both expanded and non-expanded cytotoxic CD8+ skin TRM in SJS/TEN whereas MDE displayed a cytotoxic T cell profile without expansion or recruitment of cytotoxic CD8+ T cells from circulation implicating TRM as the potential cause of disease. Concurrently, MDE displayed a pro-Treg signature, highlighted by CCR8 and TNFRSF4 (OX40), which promotes Treg survival compared to SJS/TEN.]]>
Inclusion Criteria:To be eligible for enrollment into the prospective study, individuals must:be at least 18 years of agebe able to give informed consent or have a health care proxy who is able to provide informed consent, andhave active MDE or SJS/TEN as deemed by a study staff physician (board-certified dermatologist with expertise in drug hypersensitivity reactions). Exclusion Criteria: a known allergy to Lidocaine less than 18 years of age unwilling to provide both blood and skin biopsy history of any clinically significant medical condition as determined by study staff, that may impact study analysis, including but not limited to:pregnancy or currently breastfeeding history of stem cell transplant other active skin disease at/near the site of biopsy (infection, psoriasis, atopic dermatitis/eczema, vitiligo) as determined by study staffundergoing phototherapy treatment or have used a tanning booth within 28 days of sampling. Healthy controls were obtained from leukopaks and discarded excess skin from plastics/dermatologic surgeries. There were no inclusion/exclusion criteria for healthy control samples.]]>
2018-2020]]>