CHANGCHUN, China – A collaborative research team from Jilin University, Tongji Hospital of Huazhong University of Science and Technology, and the Institute of Zoology, Chinese Academy of Sciences, has demonstrated that knocking down swine leukocyte antigen class I and II (SLA-I/II) molecules significantly mitigate human-pig xenogeneic immune rejection in vivo. The study, published in SCIENCE CHINA Life Sciences , further reveals that CD154/CD40 pathway blockade remains essential to prevent early loss of pig kidneys in non-human primates.
Xenotransplantation of pig organs presents a promising solution to address the critical shortage of human organs for transplantation. However, the robust xenogeneic immune response causing rejection of pig organs in primates has remained the principal challenge. The major histocompatibility complex class I and II molecules play crucial roles in initiating both allogeneic and xenogeneic immune responses.
In this study, the researchers generated 7-gene-edited pigs (GBC-4F) by introducing two human complement regulatory proteins (CD55 and CD46) and two coagulation regulatory factors (EPCR and TFPI) into previously established GGTA1−/−B2M−/−CIITA−/− (GBC-3KO) pig fibroblasts. These pigs showed complete absence of αGal and SLA-I/II surface expression and exhibited significantly increased resistance to human complement-dependent cytotoxicity.
In mice with human immune systems, GBC-4F pig artery grafts not only outlasted unmodified grafts but also showed five-fold weaker T-cell responses and four-fold lower antibody-mediated killing. "The SLA-I/II knockdown creates a more favorable immunological environment," said senior author Zheng Hu , a transplantation researcher at Jilin University.
In critical experiments involving rhesus monkey kidney transplantation, two monkeys without anti-CD154 treatment showed increasing serum creatinine, IgM antibody levels, and cytotoxicity, leading to euthanasia on days 17 and 19 due to severe thrombotic microangiopathy and xenogeneic humoral responses. In contrast, two monkeys receiving anti-CD154 blocking antibody maintained donor-reactive antibody levels at baseline levels and showed no signs of immune rejection for up to 70 days. These animals eventually euthanized due to surgical complications (ureteral obstruction and hydronephrosis) rather than immune rejection.
"This tells us that while silencing SLA-I/II is a major step forward, we still need to shut down co-stimulatory signals to achieve reliable early survival," said co-senior author Yong-Guang Yang of Jilin University. "It also underscores that surgical technique and infection control are just as crucial as genetic engineering for long-term success." The findings suggest that multi-pronged approaches combining extensive pig genetic modification, targeted immunosuppression, and improved clinical management will be necessary to make pig-to-human transplantation a reality.
Funding: This work was supported by the National Natural Science Foundation of China (82241224, W2441022), the National Key Research and Development Program of China (2021YFA1100700), the Jilin Province Science and Technology Development Plan (20250402003ZP), and the 2025 "Med+X" Innovation Team Project of the Bethune Medical Department of Jilin University.
Citation: Fang, M.H., Feng, H., Xu, K., Hai, T., Chen, S., Ren, J.L., Wang, W.G., Wang, Y.T., Zou, J., Xu, F., et al. (2026). Exploring primate immune responses to SLA-I/II knockdown pig xenografts in humanized mice and rhesus monkeys. SCIENCE CHINA Life Sciences . https://doi.org/10.1007/s11427-025-3162-2
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