# Investigating mechanisms of epidermal cell death in Toxic Epidermal Necrolysis

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $268,500

## Abstract

Project Summary
Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a severe drug hypersensitivity reaction
manifesting as sloughing of skin, eyes, mouth, throat and genitals, along with systemic inflammation and internal
organ involvement. Disease can occur in otherwise healthy people and is largely unpredictable. Mortality is 20-
30% and there is no known treatment. SJS/TEN is a substantial burden on the US healthcare system, costing
an estimated 129 million dollars per year. It is of paramount importance to elucidate the pathobiology of
SJS/TEN to improve disease prevention, diagnosis and treatment. Despite this clear need, SJS/TEN is
significantly under-researched. The dearth of high-quality research in this field stems from two major barriers: a
lack of patient samples available for analysis and the absence of an easily attainable and reproducible model
system to perform mechanistic studies. One major gap in our knowledge of the pathogenesis of SJS/TEN is the
putative mechanism(s) by which immune cells mediate keratinocyte death. It is largely assumed that cytolytic
granules generated by cytotoxic CD8+ T cells induce keratinocyte apoptosis. However, contradictory findings call
this assumption into question. The central hypothesis of this proposal is that the inflammatory cell death
pathways necroptosis and pyroptosis, rather than apoptosis, mediate keratinocyte death and epidermal
destruction in SJS/TEN. The proposed study will directly test this hypothesis while overcoming current barriers
in the field. Aim 1 employs two novel technologies to study a large bank of formalin-fixed paraffin embedded
clinical specimens that until now were of limited research utility. Clinical specimens are drawn from a meticulously
developed and thoroughly vetted patient database that spans three major tertiary care hospitals. These
technologies are (i) OpalTM multispectral immunofluorescence staining with MantraTM Quantitative Pathology
Imaging System and inFORM® Image Analysis Software and (ii) NanoString NCounter® platform for gene
expression profiling. Aim 2 interrogates mechanism(s) of keratinocyte death by partnering with burn teams at
two major centers to prospectively collect blister fluid and affected epidermis, a unique sample resource. Analysis
utilizes RNAseq, high parameter flow cytometry, and multiplex immunoassay in concert with traditional laboratory
techniques. Aim 3 generates a novel ex vivo model of SJS/TEN using patient blister fluid with commercially
available 3D full thickness tissue engineered human skin that will be used to investigate the proposed hypothesis
while also exploring potential novel treatments. The data generated through this innovative research has
significant potential to advance understanding of fundamental disease pathobiology and clinical care.

## Key facts

- **NIH application ID:** 9941645
- **Project number:** 1R21AI150657-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Sherrie Jill Divito
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $268,500
- **Award type:** 1
- **Project period:** 2020-08-21 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941645

## Citation

> US National Institutes of Health, RePORTER application 9941645, Investigating mechanisms of epidermal cell death in Toxic Epidermal Necrolysis (1R21AI150657-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9941645. Licensed CC0.

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