Given the gaps in knowledge that exist surrounding the basis for why these serious adverse drug reactions occur in specific patients, the Phillips lab is taking novel research strategies that for SJS/TEN specifically focus on the tissue specificity of this disease that destroys the top layer of skin (epidermis). In pursuing the specific molecular and cellular signals that are present in the skin, it is believed that the factors specifically defining the mechanistic basis of SJS/TEN and why it affects a some individuals carrying a risk gene but not others will be solved.
The key objectives of the studies that aim to advance personalized medicine approaches in serious immunologically mediated adverse drug reactions would be to 1) define a second molecular signal in the peripheral blood that clearly identifies which patients carrying a specific HLA risk allele will develop drug-induced SJS/TEN; 2) define new genes including HLA genes that are associated with drug-induced SJS/TEN and other serious immunologically mediated adverse drug reactions in different populations; 3) define biomarkers that would lead to earlier diagnosis and treatment of SJS/TEN; 4) define the molecular and cellular signals that would define new therapeutic strategies as well as the treatment that is best for a specific patient with SJS/TEN (personalized therapeutic approaches); and 5) develop diagnostic strategies to ascertain the causal drug (which drug caused the SJS/TEN), which is particularly important when patients develop SJS/TEN when they are on or have started multiple drugs concurrently. Drug-specific diagnostic strategies that are being optimized include ELISpot, with multiple cytokine outputs, intracellular cytokine staining, and flow cytometry looking for drug-specific activation of immune cells (T cells).
The Phillips lab studies the development of genetic, molecular, and cellular signals to predict and prevent life-threatening adverse drug reactions such as SJS/TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) using novel single cell technologies and mass cytometry. Her lab’s impact has been national and international, and she has forged collaborations with groups in Australia, Africa, and Southeast Asia to guide the implementation of scientific programs to study the expansive and genetically diverse drug hypersensitivity syndromes. The program is focused on human immunology and recruits patients who have had SJS/TEN and other serious immunologically mediated adverse drug reactions into research studies. These studies will collect various samples to achieve the goals above: 1) peripheral blood (PBMCs) for cellular studies, 2) bister fluid, 3) fresh skin, 4) DNA (from oral DNA collection), and 5) RNA for gene expression studies. These samples are collected from patients with serious immunologically mediated drug reactions 1) who attend the Drug allergy Clinic below, 2) patients admitted to Vanderbilt University Medical Center (VUMC), and 3) patients with serious immunologically mediated adverse drug reactions from centers outside of Vanderbilt where the samples may be processed and cryopreserved onsite and shipped to VUMC at a later date, or in the case of fresh skin, shipped to VUMC by overnight shipping for processing at VUMC. In the case of oral (saliva), DNA collection kits may be sent out to patients and returned directly to VUMC.
A second arm of the Phillips lab is directly interrogating the genetic basis of serious immunologically mediated adverse drugs reactions. This utilizes the Vanderbilt BioVU resources that house stored DNA on >250,000 patients linked to the electronic health record. Institutional review board (IRB) approval exists to do studies within this population. This BioVU resource is also a valuable source of DNA from drug tolerant patients who are needed to do genetic studies.