Harnessing translational research to advance understanding and clinical care in antibiotic allergy

Project Summary Antibiotic-induced delayed-type drug hypersensitivity reactions (dtDHR) are a major yet underappreciated public health problem, occurring commonly in skin-limited form, morbilliform drug eruption (MDE), and causing significant morbidity and mortality in severe systemic forms, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Antibiotic- induced dtDHR are significantly understudied. Consequently, understanding of immunopathogenesis has been limited, and subsequent to that, so too clinical care. The bulk of translational research in the field focuses on effector immune cell populations, most commonly T cells, as well as the role of Human Leukocyte Antigen (HLA) in pathogenesis. This narrow focus along with clinical knowledge gaps and research barriers have markedly hampered progress. Herein, we propose the potentially transformative hypothesis that some other “X-factor” is critical in driving antibiotic-induced dtDHR onset, phenotype and/or severity. We propose three possible “X-factors”: immune dysregulation via aberrant regulatory T cell response, concurrent active infection, and host microbiome. Any or all of which, if true, have potential to completely shift the paradigm of disease pathogenesis. Each factor is individually hypothesized and tested in a Specific Aim. Each Specific Aim harnesses innovative translational approaches across humans and mice to explore then directly test through highly mechanistic experimentation each hypothesis. There are two overarching experimental approaches common to all three aims. First, we perform a prospective longitudinal translational study of antibiotic-induced dtDHR patients along with matched antibiotic-tolerant controls, in which biologic samples along with comprehensive and unbiased clinical data are collected. This overcomes several knowledge gaps in the field and markedly strengthens the robustness and clinical applicability of our translational findings. Second, we exploit our own recent advances with novel mouse models and research tools to overcome prior research barriers and bolster our human experimentation. Importantly, to achieve its goals, this grant builds on ample preliminary data and the highly complementary expertise of its investigators to ensure feasibility and scientific rigor. This study’s findings have potential to profoundly impact fundamental understanding of not only antibiotic-induced dtDHR but more broadly allergy and immunology in health and disease, while also to directly transform clinical care in both the short- and long-term.