- Dr. Jeffery A. Bluestone, Principal Investigator
- Dr. Matthew D. Griffin, Co-Investigator
- University of Chicago, Chicago, USA
- Blockade of organ graft rejection by CTLA-4 ligation
Transplantation has become an established treatment for illness involving failure of function of one or more organ systems. Over the past three decades, considerable improvements have been made in short-term outcomes for all commonly transplanted organs. However, progress in overcoming the long-term limitations of transplantation has not been as successful. Chronic graft dysfunction, increased risk of infection and malignancy, and other immunosuppression-related effects such as increased vascular disease, hypertension and osteoporosis remain major limitations to the quality of life and survival of organ recipients.
The T cell response has evolved to distinguish between self and foreign tissue. Thus, exposure of the immune system to a foreign organ triggers a rejection episode mediated by antigen-specific T lymphocytes. The goal of our project is to develop new therapeutics to block the activation of the T cells that destroy the foreign organ. We have discovered that, under certain circumstances, T cell responses to foreign tissues can be modified such that they fail to respond and to not reject the transplant tissues. This phenomenon, termed tolerance, takes advantage of natural processes normally involved in regulating self-reactivity that prevents autoimmune disease in most people. Thus, treatment protocols aimed at promoting donor-specific tolerance as a replacement for life-long immunosuppression holds great promise for improving the current status of organ transplantation.
Over the past several years, we have identified a molecule on the surface of activated T cells, CTLA-4, that can shut down early events in the activation of T cells. CTLA-4 regulated transplant rejection as cardiac allograft rejection is accelerated in a rodent model following CTLA-4 blockade. This has led us to hypothesise that productive engagement of CTLA-4 during graft recognition by T cells may result in reduced immune responses to graft antigens and favour tolerance. We propose to apply gene therapy techniques to introduce innovative strategies to turn off T cells using a special form of an anti-CTLA-4 antibody that is expressed on the surface of the transplanted tissue that exploit the negative signalling properties of CTLA-4. We hope that these novel approaches will prevent graft rejection and induce tolerance in solid organ transplant recipients.