#Xenotransplantation #LiverTransplantation #GeneticallyModifiedPigLiver
The global shortage of organs hinders access to life-saving transplants,
particularly for end-stage liver diseases. In a major medical breakthrough, a
team of researchers from Xijing Hospital (China) performed a heterotopic
auxiliary xenogeneic liver transplantation by implanting a genetically modified
pig liver into a brain-dead human patient.
The objective was to assess the short-term viability, cross-species
immune tolerance, and functional capacity of a porcine liver in a human. The
graft remained functional for 10 days, demonstrating its potential as a
temporary treatment for patients with acute liver failure.
A donor pig engineered to avoid rejection
The graft came from a miniature Bama pig, genetically engineered with
six targeted modifications: deletion of genes responsible for hyperacute
rejection (GGTA1, CMAH, B4GALNT2), and addition of three human genes (CD46,
CD55, thrombomodulin) that promote graft tolerance. These modifications were
confirmed via flow cytometry, Western blot, and immunohistochemistry. The
patient, with no known comorbidities, showed no trace of porcine endogenous
viruses (PERV, PCMV). Additionally, preoperative IgG and IgM antibody levels
were low, reducing the risk of immediate rejection.
Auxiliary transplant: a bold surgical gamble
Surgeons opted for a heterotopic auxiliary approach, placing the porcine
liver outside the native hepatic system. Anastomosis of the pig’s inferior vena
cava (IVC) and portal vein to the recipient's vascular system, along with
external bile drainage, enabled stable graft function without impairing the
native human liver. This technique offers the advantage of reversibility,
making it ideal as a bridging solution while awaiting a human transplant.
Read next: One Step Closer to Pig-to-Human Xenotransplantation
A pig liver that produces bile and albumin
The xenotransplanted liver began producing golden bile within two hours
of reperfusion, reaching 66.5 mL by day 10. Porcine albumin, measured via ELISA
assay, progressively increased. Liver enzymes remained stable: alanine
aminotransferase (ALT) was within normal range, while aspartate
aminotransferase (AST) showed a transient rise. No sustained bilirubin
elevation was noted in the graft, although mild intrahepatic cholestasis was
observed in the native liver on day 10.
Hemodynamic stability and controlled coagulation
Doppler ultrasound showed adequate blood flow in the graft’s arteries
and veins, with velocities consistent with effective perfusion. Coagulation
function was closely monitored: there was a slight drop in platelets and
prolongation of APTT early on, both of which resolved by the end of the study.
The human thrombomodulin expressed in the graft may explain this effective
regulation. No leg edema was observed, indicating preserved venous return.
Tissue regeneration without immune rejection
Histological analysis revealed no signs of rejection in the pig liver.
Mild sinusoidal congestion was observed perioperatively, without signs of
chronic inflammation. By day 10, tissue regeneration markers were significantly
increased:
- Ki67, a marker of hepatocyte proliferation, was 2.5 times higher than
on day 0;
- CD31, a marker of sinusoidal endothelial cell repopulation, showed a
60% increase;
- α-SMA, indicating stellate cell activation, was reduced by 50%.
Electron microscopy confirmed the structural integrity of the porcine
liver cells, with no viral particles detected and intact microcirculation in
the sinusoids, including well-defined fenestrations in endothelial cells.
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Controlled immune response: effective T and B cell suppression
The immunosuppressive protocol included tacrolimus, mycophenolate
mofetil, methylprednisolone, and targeted agents (etanercept, rituximab). T
cells were inhibited by over 70% within the first 48 hours; B-cell activity was
effectively suppressed by rituximab, with a >60% reduction by day 5.
Pro-inflammatory cytokines remained low (IL-6 < 100 pg/mL, TNF <
500 fmol/mL, IFNγ < 20 pg/mL). IgG/IgM deposits in the graft were moderate,
with no significant activation of the complement system (C3d, C4d, C5b-9),
indicating a well-controlled immune response.
Toward a temporary bridging transplant?
This study demonstrates that a genetically modified pig liver can
survive and function in a human, at least short-term, without hyperacute
rejection. The auxiliary transplant model shows promise as a temporary solution
for patients awaiting a human liver transplant. However, the bile and albumin
volumes produced remain insufficient for long-term support. The study ended on
day 10 at the family's request, limiting long-term evaluation. Results call for
further research into orthotopic transplants and development of longer-lasting
xenografts.
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