Immune Profiles to Better Understand Chronic Allograft Dysfunction and Successful Long-term Clinical Outcomes after Human Lung Transplantation

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Project Summary/Abstract Candidate: This K23 award will support Dr. Jamie Todd's research training and accelerate her transition to independent investigation focused on improving lung transplant outcomes through prevention and treatment of chronic lung allograft dysfunction (CLAD). Dr. Todd is a physician-scientist at Duke University with clinical expertise in lung transplantation and a highly successful translational research foundation. Through this award Dr. Todd will add new expertise in immunology, immune profiling, and biostatistics and will expand her capabilities in clinical and translational research. She will master these skills through carefully mentored hands- on research experiences, completion of a Masters degree in clinical and translational research, and participation in supplementary graduate-level immunology didactics. Environment: Duke is an exceptionally well-suited environment in which to pursue this award as it combines one of the nation's largest lung transplant programs with a high level of expertise in immunology, transplant research, and translational research infrastructure. Dr. Todd's research and career development will be guided by a multidisciplinary mentorship team invested in her success including primary mentor Dr. Scott Palmer, an international leader in lung transplantation, co-mentor Dr. Kent Weinhold, an authority in immunology and immune profiling, and co-mentor Dr. Megan Neely a biostatistician with expertise in clinical and translational data analysis. Research: CLAD is the leading cause of late death after lung transplantation. Despite routine immunosuppression most, but not all, lung recipients develop CLAD. Dr. Todd's research builds upon her novel observation that CLAD can be distinguished to two clinical phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (R- CLAD) that associate with different patterns of allograft fibrosis and distinct prognoses. In this proposal Dr. Todd will pursue focused hypotheses to identify clinical risks and intragraft immune responses underlying each CLAD phenotype and to define the immune profile associated with maintenance of a CLAD-free state over long-term follow-up. Specifically in completion of this award Dr. Todd will 1) perform complementary translational and clinical studies to investigate the role of two CLAD risk factors, pulmonary aspergillus and acute rejection, on polarization toward Th2 or Th17 immunity in the allograft and the differential clinical risk for R-CLAD or BOS, respectively, and 2) define the lymphocyte profile, including regulatory T- and B-cells, in long- term CLAD-free patients as compared to those with R-CLAD or BOS. Data generated from this work will guide future R01 applications to intervene with Th2 or Th17 immune modulating agents in select lung transplant recipients so as to prevent CLAD and use allograft or peripheral blood immune signatures to predict lung recipient outcomes or treatment responses. This mentored research will accelerate Dr. Todd's career goal of independent investigation in lung transplantation with a focus on preventing CLAD, promoting successful long- term posttransplant outcomes, and enabling personalized lung recipient care.