The goal of this mentored fellowship training grant is to facilitate my acquisition of knowledge of complex pathophysiologic systems, advanced laboratory techniques, and scientific study design that will aid in my ability ultimately to become an independent clinician-investigator. My current fellowship training program in Infectious Diseases has provided in-depth clinical experience with the diagnosis and management of sepsis among both immunocompetent patients and transplant recipients, and has fostered a keen interest in scientific research in this area. The proposed training program utilizes the extensive experience of mentors Dr. Coopersmith and Dr. Ford to establish a unique multidisciplinary team well-suited to broaden my knowledge base, expand my technical skills, and provide experience with experimental design and scientific writing. Sepsis affects over 800,000 patients per year and is the leading cause of death in the intensive care unit. Immunocompromised patients such as transplant recipients have a higher incidence of developing sepsis as well as increased morbidity and mortality from the disease. Significantly less is known about whether the development of sepsis directly affects the risk of graft failure. Organs have become an increasingly precious resource as transplantation is utilized for curing end-stage organ failure from many etiologies. Effective treatment of transplant recipients with sepsis is dependent not only upon pathogen eradication but also abatement of the immune dysregulation of sepsis and minimizing the risk of graft rejection. Currently, it is not known if te immune dysfunction of sepsis directly predisposes to graft rejection, but there are many similarities in the pathways of T cell activation and cytokine responses between the two processes. Furthermore, as investigation into immunomodulatory therapies for sepsis is increasing, it is important to understand the interaction between the immune responses to sepsis and the activation of alloreactive T cells that compromise graft survival. Given the increasing interest in immunomodulatory agents for the treatment of sepsis, the immune response to sepsis in the setting of a transplant must be understood to determine what therapies may be appropriate for this population in an effort to simultaneously combat the initial infection, ameliorate the immune dysfunction of sepsis, and preserve graft function.
Over 890,000 people develop sepsis each year, and immunocompromised states are a well-recognized risk factor for morbidity and mortality from the disease. Roughly 28,000 organs are transplanted yearly, and these patients are at high risk for infectious complications given the necessity of immune suppression to combat graft rejection. Currently, little is known about the pathophysiology of sepsis in transplant patients or the effects of sepsis on graft rejection, and the experiments outlined in this proposal will investigate the mechanisms by which sepsis may predispose to graft failure.