The UCSF Liver Disease Program excels in all areas of research. Its broad portfolio of basic science and clinical outcomes research includes fetal surgery, transplantation immunology, tissue engineering, immunogenetics, vascular biology, trauma prevention, wound healing, genomics, cancer biology, and neurobiology of digestive diseases.
The UCSF Liver Disease Program excels in a broad range of research. Its portfolio of basic science and clinical outcomes research includes fetal surgery, transplantation immunology, tissue engineering, immunogenetics, vascular biology, trauma prevention, wound healing, genomics, cancer biology, and neurobiology of digestive diseases.
An essential function of the immune system is the regulation of its own activities to refrain from attacking healthy tissues and to contract after successful elimination of pathogens. Research in the past decade has shown that much of the self-control of the immune system can be attributed to a small population of white blood cells called regulatory T cells (Tregs). One of our current studies is investigating how Tregs prevent autoimmune diabetes and transplant rejection in a mouse model system.
Another potentially important tool for achieving allo-specific tolerance is the dendritic cell (DC). DCs are specialized cells that bind to and activate the T cells that cause rejection. We are conducting ongoing experiments in which we have succeeded in genetically engineering DCs to express well-known immunomodulatory molecules (interleukin 10, TGF-beta, CTLA4 Ig). These modified DCs appear to specifically inhibit donor-specific T cells in vitro. A major emphasis of our work is targeting DCs to lymphoid organs (such as lymph nodes and spleen) via engineered expression of lymphoid homing receptors. We believe that lymphoid homing will be critical to the induction of tolerance.
Principal Investigators in the Transplantation Research Lab are also currently conducting several human research studies to evaluate the efficacy and safety of newly developed immunosuppressive agents. These studies aim to determine successful regimens with substitute anti-rejection drugs, while avoiding the severe negative side-effects associated with chronic use of existing drugs such as calcineurin inhibitors (CNIs). Inherent toxicities of CNIs may be contributing to long-term patient death and kidney failure.
One promising immunosuppression treatment for liver transplant recipients that is now being investigated in clinical trials is a drug called belatacept. Belatacept, with a novel mechanism of action that provides greater specificity of effect, is non-nephrotoxic and has been shown in several primate models to successfully inhibit the primary immune responses to the allografts without inhibiting the immune system to the point that viral infection or reactivation occurs.
A second novel treatment that is being studied for use as prophylaxis of graft failure is gaseous carbon monoxide for inhalation. Carbon monoxide modulates several intracellular signaling pathways and generates increased levels of anti-inflammatory molecules.
Another goal of current clinical studies is to analyze the effects of withdrawal from immunosuppressive drugs. The clinical and mechanistic outcomes of attempting withdrawal are compared to those in groups whose standard treatments are maintained, the objective being to establish how best to manage immunosuppression in various types of patients.