Research Group

  • Prof. Herman Waldmann, Principal Investigator
  • Dr. Kathleen Nolan, Research Associate
  • Dr. Paul Fairchild, Research Associate
  • Dr. Stephen Cobbold, Research Associate
  • Mr. Mark Frewin, Research Associate
  • Mrs. Sue Humm, Research Associate

Location

  • Oxford University, Oxford, UK

Title

  • Gene Expression in Tolerogenic Dendritic Cells

The immune system is geared to react to dangerous foreign microbes. Such microbes are displayed or “presented” to the immune system on specialised antigen-presenting cells which, based on their morphology, are known as dendritic cells. Rejection of transplanted organs results from graft antigens being wrongly perceived as "dangerous" because the dendritic cells displaying them are driven into alert mode. Recent evidence suggests that dendritic cells that are either immature, quiescent or pharmacologically restrained may indeed not immunise the host, but instead direct the host immune system towards permanently tolerating that tissue.

Harnessing tolerance processes is one of the most desirable goals in transplantation because it would spare the use of immunosuppressive drugs that penalise the whole immune system, risking infections and cancer, as well as the many other side effects associated with these drugs.

For this reason we would like to know the differences in the genes expressed by tolerogenic populations of DC compared with their activated counterparts. Such differentially expressed genes should provide clues as to the proteins that determine immunity rather than tolerance.

The host laboratory has created a wide range of “gene libraries” of dendritic cell populations as a baseline for such an analysis. The aim of this proposal is to expose dendritic cells to a range of pharmacological agents that are known to promote tolerance, and to determine through construction of new libraries, which gene products are lost and which gained. By testing candidate genes or their inhibitors in simple readouts of immune responsiveness it should be possible to establish which sets of gene changes are important to tolerance. This information may lead to improved strategies for modifying the way the immune system perceives transplants so as to ensure that it becomes reprogrammed to recognise them as "friendly".