Translational Research: Transplant Immunology

Overview

The Division of Abdominal Transplantation is actively engaged in both clinical and basic science research. This research includes faculty, fellows, residents, graduate students, postdoctoral fellows and medical students. The Division’s research laboratories are located in the MSLS building on Welch Road.

Transplantation is also part of the Immunity, Transplantation and Infection Institute at Stanford University (ITI), which investigates the immune system’s role in health and disease, including transplantation.

~Functions of microRNAs in transplantation
~Identification and function of NK cells
~Apoptosis and tissue damage in transplantation and liver disease

Transplant Tolerance

Solid organ transplantation is a life-saving procedure however graft rejection, and other adverse effects associated with immunosuppressive drugs do still pose significant challenges. Nevertheless, there is widespread agreement that some graft recipients are “operationally tolerant” and could maintain their graft without the need for immunosuppression. The major gap in the field is finding a method to identify those patients that would retain healthy graft function without immunosuppression. Our goal is the development of a rapid blood-based test, or biomarker, that indicates “operational tolerance” (stable graft function without the need for immunosuppression). We are utilizing cutting edge mass cytometry technology, termed Cytometry Time of Flight (CYToF), to acquire a previously unattainable picture of the immune system in patients who have been removed from immunosuppression for a variety of reasons but who maintain good graft function. We have identified a novel cell population, the T cell of Operational Tolerance "TOT", distinguished by surface marker expression of CD3+CD4+CD5+CD25+CD38-/lowCD45RA- that is a hallmark of tolerance in transplant recipients.

MicroRNAs as Immune Regulators in Transplantation

MicroRNAs are increasingly recognized as master regulators of gene transcription in cells. We were the first to demonstrate the functional significance of microRNAs in alloimmune responses and transplantation. We demonstrated that one microRNA, miR-182 was significantly increased, in the CD4T cells in rejecting allografts and further showed that miR-182 targets FOXO1, a member of the Forkhead box (FOX) protein family of important transcription factors. Modulation of miR-182 increases FOXO1 expression and prolongs graft survival by altering T cell activation and decreasing graft infiltration. Importantly, not only is the microRNA miR-182 increased in the allograft, it is also significantly elevated in the blood during graft rejection. MicroRNAs have remarkable stability in blood thus miR-182 may prove to be a specific biomarker of graft status and could be developed as a non-invasive harbinger of graft function. More recently we has identified a microRNA that is expressed by tolerogenic plasmacytoid dendritic cells (pDC) and is necessary for the prolongation of allograft survival.

Clinical Trials

Biomarkers for Post-Transplant Lymphoproliferative Disorders in Children

Solid organ transplantation is an important therapeutic option for children with a variety of end stage diseases. However, the same immunosuppressive medications that are required to prevent the child's immune system from attacking and rejecting the transplanted organ can predispose these individuals to developing a very serious cancer that is linked to Epstein-Barr virus (EBV).

There are two major areas of focus in the laboratory. First, we are interested in Epstein Barr Virus-mediated mechanisms of immune evasion with particular focus on pathways that promote survival and proliferation of EBV B cell lymphomas, the characterization of the human T cell response to EBV-infected B cells and the identification of novel therapeutics for treatment of EBV B cell lymphomas. The second area of study addresses stem cell and solid organ transplantation. In particular we are examining mechanisms of graft rejection and immune regulation in allogeneic responses.

Clinical Trials

Biomarkers for Post-Transplant Lymphoproliferative Disorders in Children

Solid organ transplantation is an important therapeutic option for children with a variety of end stage diseases. However, the same immunosuppressive medications that are required to prevent the child's immune system from attacking and rejecting the transplanted organ can predispose these individuals to developing a very serious cancer that is linked to Epstein-Barr virus (EBV).