Despite all the advances in lung transplantation, we still have no effective non-invasive methods for assessing the immune function of lung transplant recipients. The standard method for assessing the immune function of lung transplant recipients remains the surveillance bronchoscopy with trans-bronchial biopsy, a procedure that carries a small but real risk of morbidity. Current immune-suppression practices are protocol based, where recipients receive the same immunosuppression, mostly based on their time from transplant. This approach however, does not take into account the considerable variability in pharmacokinetics, pharmacodynamics and underling immune strength which is observed between patients. This protocol based approach leads to unnecessary morbidity and mortality due to both over-immunosuppression (infection, malignancy, toxicity) and under-immunosuppression (acute rejection). Importantly, each episode of infection and acute rejection increases the risk of Chronic Lung Allograft Dysfunction (CLAD), the major factor limiting survival after lung transplantation. The objective of this prospective study is to determine if plasma CXCR3 chemokines (CXCL9, CXCL10, CXCL11) can be used to non-invasively diagnose episodes of acute rejection and identify recipients at increased risk of developing CLAD. The successful completion of these aims would improve our current management of lung transplant recipients by minimizing the need for surveillance transbronchial biopsies, allowing for early non-invasive diagnosis of acute rejection and tailoring of immune suppression regimens to serial measurements of actual immune function. This proposal is the ideal springboard into my independent career and R01 application conducting a clinical trial tailoring an individual?s immunosuppression regimen to serial biomarker(s) measurements as a method to minimize the incidence of acute rejection, pneumonia and CLAD. My prior work experience, Master of Science in Clinical Research and clinical training in lung transplantation make me uniquely suited for the current proposal. However, I require additional training in three critical areas to successfully complete the current aims and transition to independent investigation: molecular/cellular biology techniques, advanced statistical methods and clinical trial design. During this award period, I will acquire new skills which will improve my ability to assess the bioactivity of chemokine pathways and immune function after lung transplantation, statistically model complex data, optimize diagnostic performance of biomarkers, conduct biomarker validation studies as well as clinical trials implementing their use. My career development plan takes full advantage of the resources available at UCLA, including coursework, Center of Immunogenetics, Departments of Pathology and Biomathematics, scientific and career development seminars, as well as the internationally recognized expertise of my mentors and collaborators.
TO PUBLIC HEALTH: Chronic rejection or chronic lung allograft dysfunction (CLAD) is the leading cause of death after the first year and the major factor limiting long-term survival. This proposal will investigate the use of plasma CXCR3 chemokines for the non-invasive diagnosis of acute rejection and identification of lung transplant recipients at increased risk of CLAD development. The successful completion of these aims would significantly improve the current management of lung transplant recipients and decrease the incidence of CLAD development.