Ectopic lymphoid tissue development in chronic allograft vasculopathy. (360G-Wellcome-084440_Z_07_Z)

The aims of this project are three-fold: to clarify how frequently ectopic lymphoid tissue (ELT) occurs within heart grafts and whether its presence correlates with development of chronic allograft vasculopathy (CAV), to examine how graft-ELT functions independently of conventional secondary lymphoid organs (SLOs), and to assess whether blocking ELT formation abrogates CAV development. Foci of ELT are frequently found in explanted failed solid organ transplants. In autoimmunity, immune respon ses originating within ELT may drive disease progression. Whether allograft-ELT responses similarly influence graft survival is, however, unknown. ELT formation will be studied in two mouse models of chronic cardiac allograft rejection. Heart allografts will be excised 50 days after transplantation and the presence of ELT correlated with the degree of CAV. To distinguish the alloimmune response in ELT from conventional SLOs, mice that lack SLOs will receive previously transplanted heart graft s and activation of na ve alloreactive T and B cells, dependent upon graft-ELT, assessed. These experiments will be extended to examine whether graft-ELT is a site for alloreactive T cell epitope spreading and alloreactive B cell somatic hypermutation. Monoclonal antibodies will be used to block key signalling pathways required for ELT formation and their effect on CAV development determined.