This application for a Mentored Clinician Scientist Development Award (K08) is designed to evaluate the effect of cirrhosis-induced immune dysfunction on liver transplant outcomes. The candidate is a transplant surgeon and immunologist whose long-term goal is to develop treatments to prevent immune frailty and improve liver transplant recipient survival. In order to fulfill the educational objectives of this award, this proposal will expand the applicant?s knowledge base into novel lines of translational research inquiry and delve into new areas of investigation requiring focused mentorship. The mentors assisting in the applicant?s development will be crucial for her success, for the performance of the proposed studies, and for the educational mission of the award. Xian Li, PhD, a leader in basic science immunology, and Mark Ghobrial, MD, PhD, a leader in clinical and translational research, will serve as co-mentors. They will be assisted by Drs. Dale Hamilton and Anisha Gupte, who will provide mentorship in bioenergetics; Dr. Ed Graviss, who will provide expertise in biostatistics; Dr. Wenhao Chen, who will provide expertise in T cell exhaustion, and Dr. Todd Eagar, who will provide expertise in inflammation. A rigorous career development plan will be implemented, including structured workshops, biostatistics course work, scientific seminars, and lab meetings. This combination will be instrumental in ensuring the candidate?s successful transition to a career as an independent investigator. PROJECT SUMMARY: Due to organ shortage, livers are transplanted in order of recipient medical urgency; however, ethical principles dictate avoidance of futile transplantation. Due to imbalance in supply and demand for organs, illness severity (categorized by MELD score) has drastically increased. MELD does not correlate well with risk of death post-transplant; thus, better metrics to evaluate risk of mortality are necessary. The most common cause of death early after liver transplant relates to consequences of an immune system which is frail or dysfunctional prior to transplant. In pre-transplant cirrhotics, immune frailty may relate to metabolic deficiencies or T cell exhaustion and may affect liver transplant outcomes. Based on this, it is hypothesized that the pre-transplant state of immunologic frailty results from cirrhosis-related alterations in recipient metabolism, resulting in global T cell metabolic dysfunction, increased T cell exhaustion, and limited adaptive immune proliferation and function. Persistence of immunologic frailty following liver transplant results in increased recipient mortality. This will be addressed by three Aims, which will (1) evaluate metabolic alterations in liver transplant recipients and determine the bioenergetics pathways involved in immune frailty, (2) examine the role of T cell exhaustion in immune frailty, and (3) determine the longitudinal effect of frailty on the recipient post-transplant immune response. IMPACT: These studies are critically important to identify biological markers of immunologic frailty. Defining pre- transplant frailty will improve patient selection for liver transplant, prevent wasting of livers in patients at high risk of futility, and identify therapeutic targets to reverse frailty and improve patient survival.
The overall goal of this project is to develop an understanding of the pre-transplant state of immune dysfunction (or immunologic frailty), which exists in patients with severe cirrhosis. This state of immune dysfunction is the primary cause of recipient death within the first year of transplant, because it results in increased infections, sepsis, recurrent malignancy, post-transplant lymphoproliferative disease, and graft versus host disease. Defining this state of immunologic frailty will improve patient selection for liver transplant, prevent wasting of livers in patients at high risk of futile liver transplant outcomes, and identify therapeutic targets to reverse frailty and improve patient survival after liver transplant.
