Saturday September 25, 2021 - 19:00 to 20:00
Early interferon-gamma response in nonhuman primate recipients of solid organ xenotransplantation
Hee Jung Kang1, Eun Mi Park1, Haneulnari Lee1, Keon Bong Oh2, Jun Seok Kim3, Hyun Keun Chee3, Jung-Hwan Park4, Kyoung Sik Park5, Ik-Jin Yun5.
1Laboratory Medicine, Hallym University College of Medicine, Anyang, Korea; 2Animal Biotechnology Division, National Institute of Animal Science, Jeonju, Korea; 3Thoracic and Cardiovascular Surgery, Konkuk University School of Medicine, Seoul, Korea; 4Nephrology, Konkuk University School of Medicine, Seoul, Korea; 5Surgery, Konkuk University School of Medicine, Seoul, Korea
Background: To understand changes in biological responses in nonhuman primate (NHP) recipients of xenotransplantation (XTP), we retrospectively investigated chronological changes in cytokine profiles of NHP recipients after solid organ XTP.
Methods: Plasma samples were collected from 7 NHP recipients of pig heart or kidney XTP with alpha-1,3-galactosyltransferase gene knockout (GTKO) under anti-CD154-based immune suppression at the following time points: immediately before; after 2 h, 3 d, and 7 d of XTP; and weekly thereafter until the graft failed. The plasma levels of the following cytokines were measured: interleukin (IL)-1α, IL-1β, IL-6, IL-12p70, IL-8, IL-10, IL-15, tumor necrotizing factor, interferon-gamma (IFN-γ), D-dimer, C3a, histone-complexed DNA fragments, and porcine high mobility group box 1. For in vitro experiments, human natural killer (NK) cells were co-cultured with wild-type (WT)-porcine endothelial cells (PECs), GTKO-PECs, and human umbilical vein endothelial cells (HUVECs), with or without anti-CD154 antibody. IFN-γ levels in the culture supernatants were compared.
Results: IFN-γ levels peaked on day 7 or 10 of XTP and then decreased to basal levels, whereas proinflammatory cytokine levels increased along with the elevation of histone-complexed DNA fragments and were sustained until xenograft failure. In vitro, human NK cells produced more IFN-γ when in contact with WT-PECs than with HUVECs, which was not reduced by the use of GTKO-PECs or addition of anti-CD154 antibody into the mixture.
Conclusions: In NHP recipients of XTP, the early peak of IFN-γ priming subsequent inflammatory responses may be attributed to NK cell activation in response to xenografts.
This work was carried out with the support of “Cooperative Research Program for Agriculture Science and Technology Development (Project No. PJ013842 and PJ015607)” Rural Development Administration, Republic of Korea. This research was partly supported by Hallym University Research Fund. .