Role of tryptophan metabolism in liver transplant tolerance and rejection

Funded Activity Summary

Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown that acceptance is due to donor white blood cells transferred with the liver and based on this finding we are developing treatments that can be used in transplant patients. The current application for funding tests another breakthrough that we have recently made, that treatment of the recipient with a substance called 1-methyltryptophan prevents liver acceptance. 1-methyltryptophan prevents the activity of an enzyme called indoleamine dioxygenase, which we have shown to be increased in liver recipients that accept their graft. This is strong evidence that indoleamine dioxygenase is involved in liver transplant tolerance. These findings show that liver acceptance should be improved by increasing the levels of indoleamine dioxygenase at the time of transplantation. The aim of the current application is to examine whether increased levels of indoleamine dioxygenase expression in the transplanted liver can lead to an improved outcome. We will use two novel techniques to increase expression: gene therapy or treatment of the donor with IL-4. For gene therapy, an expression system will be used that we have recently shown is specific for the liver. In current NHMRC-funded experiments we have shown that IL-4 treatment of donor liver leads to marked increases in indoleamine dioxygenase expression. Ultimately it is intended that these findings will be used to prolong the survival of liver transplant patients by revealing new ways to prevent rejection of liver transplants.

Funded Activity Details

Start Date: 01-01-2007

End Date: 01-01-2009

Funding Scheme: NHMRC Project Grants

Funding Amount: $401,203.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Medical and Health Sciences

ANZSRC Socio-Economic Objective (SEO)

There are no SEO codes available for this funding activity

Other Keywords

acute allograft rejection | gene therapy | indoleamine 2,3 dioxygenase | liver | liver disease | liver transplantation | transplantation tolerance | tryptophan metabolism

Related Links