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Discovery of non‐HLA antibodies associated with cardiac allograft rejection and development and validation of a non‐HLA antigen multiplex panel: From bench to bedside
Author(s) -
Butler Carrie L.,
Hickey Michelle J.,
Jiang Ning,
Zheng Ying,
Gjertson David,
Zhang Qiuheng,
Rao Ping,
Fishbein Gregory A.,
Cadeiras Martin,
Deng Mario C.,
Banchs Hector L.,
Torre Guillermo,
DeNofrio David,
Eisen Howard J.,
Kobashigawa Jon,
Starling Randall C.,
Kfoury Abdallah,
Van Bakel Adrian,
Ewald Gregory,
Balazs Ivan,
Baas Arnold S.,
Cruz Daniel,
Ardehali Reza,
Biniwale Reshma,
Kwon Murray,
Ardehali Abbas,
Nsair Ali,
Ray Bryan,
Reed Elaine F.
Publication year - 2020
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15863
Subject(s) - medicine , human leukocyte antigen , immunology , antibody , multiplex , panel reactive antibody , antigen , alloimmunity , transplantation , biology , bioinformatics
We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non‐HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody–negative, endothelial cell crossmatch–positive sera obtained from 12 cardiac allograft recipients at the time of biopsy‐proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non‐HLA antibodies associated with rejection ( P < .1) including 4 newly identified non‐HLA antigenic targets ( DEXI, EMCN, LPHN1 , and SSB ). CART analysis showed 5/18 non‐HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non‐HLA antigens synergize with HLA donor‐specific antibodies and significantly increase the odds of rejection ( P < .1). The non‐HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 ( P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non‐HLA antibodies identifies cardiac transplant recipients at risk of rejection.