Preventing rejection of transplanted organs without using immunosuppressive drugs

Summary

The project aims to identify molecular pathways to prevent rejection of transplanted organs in animal models and to apply these findings to clinical transplantation.

Supervisor(s)

Dr Alex Bishop

Research Location

Bosch Institute (Collaborative Transplantation Group)

Program Type

Masters/PHD

Synopsis

The major complication of organ transplantation is rejection and one aim of the Collaborative Transplantation Research Group is to identify ways to prevent rejection. Our approach is to identify molecular pathways by which the rejection response can be abrogated such as the immunomodulatory genes CTLA4, indoleamine dioxygenase (IDO) and interleukin-4.

We have been investigating animal models of transplantation to identify these pathways and have established several models in which, paradoxically, the transplanted organ is not rejected despite a strong incompatibility between donor and recipient. These models allow us to identify genes and pathways that operate in transplant acceptance compared to rejection.

In collaboration with the Gene therapy Group at the Children's Hospital, Westmead we have established techniques for expressing immunomodulatory genes in rat liver. The liver is then transplanted to test whether this gene expression prevents liver transplant rejection. We have also found, in collaboration with the Immune Tolerance Group, University of New South Wales, that donor treatment with recombinant rat IL-4 prevents liver transplant rejection and we are currently examining the mechanism. In collaboration with the Vascular Biology Laboratory at The University of Sydney we are investigating the effect of heart transplant rejection on generalised vascular endothelial dysfunction.

The projects, which are supported by a grant from the National Health and Medical Research Council, involve cloning and expression of genes such as IDO, CTLA4 and PDL-1 in rat liver to examine whether their expression prolongs survival. They also involve examination of transplanted organs and tissues from the recipient to identify the processes of rejection and tolerance. Strategies that induce acceptance in rodent models will be tested in large animal models for suitability for clinical trial.

Additional Information

The techniques to be used include molecular cloning, production of adeno-associated viral vectors, immunohistochemistry, real time PCR analysis, tissue culture and flow cytometry. Possible research topics include:

  • Transgenic expression of immunomodulatory molecules in donor liver as a means to prevent liver transplant rejection
  • Role of immunomodulatory molecules and mast cells in IL-4-induced liver transplant acceptance
  • Vascular endothelial cell dysfunction and its role in acute and chronic heart allograft dysfunction.
  • Signalling through the common gamma chain of the cytokine receptor and its involvement in organ transplant tolerance and rejection
Funding: Some scholarships are available through the Collaborative Transplantation Research Group to selected applicants with an interest in transplantation research.

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Keywords

Transplantation tolerance, end organ damage, liver failure, end-stage renal disease, Organ transplantation, Graft rejection, transplantation, immunological tolerance, Gene therapy, Liver disease, interleukins, indoleamine 2, 3 dioxygenase, Organ replacement, Cell biology, Human body, Infection & immunity

Opportunity ID

The opportunity ID for this research opportunity is: 236