- Dr. Eleanor Bolton, Principal Investigator
- Mr. Gavin Pettigrew, Co-Investigator
- Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
- The Role of B Lymphocytes in Chronic Transplant Rejection
This research project seeks a clearer understanding of the cellular and molecular processes resulting in rejection of transplanted tissues from genetically unrelated individuals. It is known that the different pathways (direct and indirect) through which foreign antigens expressed by donor tissues are processed and presented to recipient T cells influence the resulting pattern of graft rejection (acute and chronic). It is also generally accepted that the direct pathway of recognition is associated more with acute rejection which is easier to control with immunosuppressive drugs, while the indirect pathway contributes to chronic graft rejection for which there are currently no effective treatments.
Chronic rejection is now the major reason for transplant failure. Chronic allograft rejection is characterised by increasing obliteration of the lumen of blood vessels in the graft as a result of proliferation of intimal cells lining the vessels. This graft vasculopathy is thought to be mediated in part by antibodies recognising intact donor antigens expressed by the graft. It is unclear, however, how presentation of processed donor antigen via the indirect pathway during the recognition phase following transplantation can result in generation of antibodies that recognise intact, non-processed donor antigen as a target molecule in the effector phase resulting in graft destruction. We propose a novel hypothesis that B lymphocytes, which have receptors for intact donor antigen, may function as both antigen-presenting cells and antibody-secreting effector cells thereby contributing to chronic allograft vasculopathy.
We propose to use novel strains of transgenic mice in cardiac transplant experiments. The presence or absence of selected B cell antigens and transplantation (MHC) antigens in different strains of donor and recipient mice will influence the survival time of heart transplants. The relative effects on graft rejection will be analysed by cellular assays, including the Elispot assay, by antibody analysis and by studying the pathology and immunohistology of transplanted tissues. These studies will enable us to dissect the cellular and molecular interactions that may permit B lymphocytes to function as antigen-presenting cells. They may result in the rational design of strategies for inducing B cell tolerance, thereby diminishing the risk of chronic graft rejection.