Research & Publications
While recent advances have improved rates of early allograft loss, late allograft loss occurring >1 year post-transplantation remains medically untreatable and accounts for an annualized rate of graft loss of ~4%. Late allograft loss is most commonly attributed to chronic antibody-mediated rejection (CABMR), a condition characterized by vascular complications including complement activation and vasculopathy, i.e., development of vaso-occlusive lesions leading to ischemic complications.
Complement are a set of circulating immune proteins involved in host defense that critically mediate CABMR. Upon terminal activation, complement proteins self-assemble into transmembranous pores called membrane attack complexes (MAC). MAC insert into surfaces of endothelial cells (ECs), the cells that line blood vessels, to trigger inflammation. We used sera from allo-sensitized transplant candidates to model the effects of complement, and we discovered an endosome-based signaling mechanism activated by MAC that resulted in activation of at least three pro-inflammatory pathways, non-canonical NF-kB, NLRP3 inflammasomes, and canonical NF-kB in ECs. These pathways collectively activated a broad range of inflammatory molecules and potentiated the ability of ECs to activate alloimmune CD4+ T cells. Our laboratory has developed novel assays to explore this endosome-associated pathway in cultured human EC, in two humanized mouse models reproducing clinical features of CABMR, and in patient biospecimens. We believe this pathway is broadly relevant to many complement-mediated conditions and as such may represent an attractive therapeutic target.
Our current areas of research includes: 1) determining endosome-associated signaling components(s) required for complement to induce EC activation, and 2) identifying CD4+ T cell subset(s) that may be activated by MAC-bound ECs. We have a number of ongoing translational projects in each of these areas that are very exciting. Please contact me if you have an interest in any of the above.
Endothelium, Vascular; Transplantation Immunology; Heart Transplantation