- Dr. Robert Colvin, Principal Investigator
- Dr. Paul S. Russell, Co-Investigator
- Dr. Shuichiro Uehara, Research Associate
- Ms. Catharine Chase, Laboratory Supervisor
- Ms. Patricia DellaPelle, Senior Technologist
- Dr. Dennis Sgroi, Collaborator
- Dr. Michael Carroll, Collaborator
- Massachusetts General Hospital, Boston, USA
- Mechanisms of Antibody-Mediated Chronic Rejection in Mouse Cardiac and Kidney Allografts
Late graft loss remains a substantial obstacle to long-term success in organ transplantation. Prevention and treatment requires identification of the cause and understanding of the mechanisms of late graft injury. Recent studies in humans indicate that a substantial fraction of late graft failure is associated with formation of antibodies to the donor, deposition of complement (C4d) in graft vessels and chronic arterial and glomerular damage. Direct proof that antibodies cause these lesions is lacking, as well as the mechanism by which they might do so.
The goal of this project is to prove which lesions considered "chronic rejection" can be caused by antibodies and to determine the relevant molecular mechanisms by which they arise. Here we will develop a suitable experimental model, using well-characterized mouse models of heart and kidney transplantation in genetically defined strains to determine which of the chronic lesions can be initiated by antibody. We will analyze the cellular components and the evolution of the lesions and determine whether the endothelial cells express molecules that might serve to resist the injurious effects of antibody and complement. We will determine whether chronic tissue injury by antibody requires complement fixation, binding of antibody to cells (Fc receptors) or certain other mediators such as interferon-γ. Systematic study of gene expression promoted by antibody to donor endothelial cells in vivo will be done using isolated tissue obtained by laser capture microdissection and DNA microarrays. The results should provide clear insights into the possible role of antibodies in graft rejection in humans and may help identify new strategies of intervention.