Detailed experimental protocols are reported in the Expanded Materials and Methods section in the online supplement. All experiments using human materials were approved by the relevant Institutional Review Boards and those involving animals by the Yale Institutional Animal Care and Use Committee. In vitro studies of human EC responses were conducted using multiple different isolates of serially passaged HUVEC pretreated with IFN-γ to restore in situ levels of class I and class II HLA molecule expression. De-identified high titer PRA sera were obtained from the Yale-New Haven Hospital HLA typing lab. HUVEC responses to PRA sera, control sera, components of these sera, isolated complement components or other agents were assessed by flow cytometry, immunofluorescence microscopy, Western blotting, reporter genes, expression microarrays, or real time quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR). CD4+ memory T cells were isolated from peripheral blood mononuclear cells collected by leukapheresis and interactions with EC were analyzed for adhesion under flow or for activation in response to direct recognition of non-self HLA molecules by flow cytometry or ELISA. De-identified human renal allograft biopsies were analyzed by immunofluorescence microscopy. Responses of human artery xenografts in immunodeficient mice were analyzed by histology, morphometric analyses, immunofluorescence microscopy, and qRT-PCR. Student’s t-test, ANOVA, and Mann-Whiteney analyses were performed using Origin computer software (Northampton, MA). Two-sided p-values are presented in the text with p-values <0.05 considered significant.