Date of Award
Medical Doctor (MD)
Perioperative ischemia reperfusion injury (IRI) is a consequence of solid organ allograft transplantation that primes the graft for future rejection. Using humanized in vitro and in vivo models of IRI previously developed in the Jane-wit lab, we found that IRI-like treatment of human umbilical vein endothelial cells causes non-lytic terminal complement deposition and subsequent up-regulation of co-stimulatory molecules including ICOS-L and PD-L2, replicating findings from human renal biopsies with confirmed complement deposition. Because ICOS-L and PD-L2 are cognate ligands of surface markers for both follicular T helper cells (Tfh) and peripheral T helper cells (Tph), we investigated how these T cell subsets respond to IRI-treated endothelial cells. In co-culture, IRI-treated endothelial cells induced selective expansion of Tph compared to Tfh cells (p<0.01) and production of donor specific antibodies by B cells. In vivo, IRI-mediated complement activation caused increased infiltration by Tph but not Tfh into the neo-intima (p<0.05), and resulted in the production of anti-HLA antibodies. These findings represent a mechanistic link between IRI-induced complement activation and future antibody-mediated rejection.
Fu, Whitney, "Ischemia-Reperfusion Injury-Mediated Complement Activation Of Endothelial Cells Leads To Expansion Of Peripheral T Helper Cells And Production Of Donor Specific Antibodies" (2019). Yale Medicine Thesis Digital Library. 3494.