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Histopathology of pig kidney grafts with/without expression of the carbohydrate Neu5Gc in immunosuppressed baboons
Author(s) -
Foote Jeremy B.,
Jagdale Abhijit,
Yamamoto Takayuki,
Hara Hidetaka,
Bikhet Mohamed H.,
Schuurman HenkJan,
Nguyen Huy Q.,
Ezzelarab Mohamed,
Ayares David,
Anderson Douglas J.,
Fatima Huma,
Eckhoff Devin E.,
Cooper David K. C.,
Iwase Hayato
Publication year - 2021
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/xen.12715
Subject(s) - xenotransplantation , baboon , biology , antibody , kidney , histopathology , transplantation , peripheral blood mononuclear cell , immunohistochemistry , immunology , pathology , medicine , endocrinology , biochemistry , in vitro
Abstract Introduction Pigs deficient in three glycosyltransferase enzymes (triple‐knockout [TKO] pigs, that is, not expressing the three known carbohydrate xenoantigens) and expressing ‘protective’ human transgenes are considered a likely source of organs for transplantation into human recipients. Some human sera have no or minimal natural antibody binding to red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs. However, all Old World monkeys exhibit natural antibody binding to TKO pig cells. The xenoantigen targets of Old World monkey natural antibodies are postulated to be carbohydrate moieties exposed when the expression of the carbohydrate N‐glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival in baboons and histopathology of renal grafts from pigs that either (a) expressed Neu5Gc (GTKO pigs; Group 1 ) or (b) did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group 2 ). Methods Life‐supporting renal transplants were carried out using GTKO ( n = 5) or DKO/TKO ( n = 5) pig kidneys under an anti‐CD40mAb‐based immunosuppressive regimen. Results Group 1 baboons survived longer than Group 2 baboons (median 237 vs. 35 days; mean 196 vs. 57 days; p < 0.07) and exhibited histopathological features of antibody‐mediated rejection in only two kidneys. Group 2 exhibited histopathological features of antibody‐mediated rejection in all five grafts, with IgM and IgG binding to renal interstitial arteries and peritubular capillaries. Rejection‐free survival was significantly longer in Group 1 ( p < 0.05). Conclusions The absence of expression of Neu5Gc on pig kidney grafts is associated with increased binding of baboon antibodies to pig endothelium and reduced graft survival.