Background:

We have previously shown that the accelerated anti-donor immune response is related to the portal hypertension (PH) that develops after living-donor liver transplantation (LDLT), especially in the case of small-for-size grafts (SFSGs). In addition, we previously reported that liver sinusoidal endothelial cells (LSECs), which express MHC class II and co-stimulation molecules, induce donor-specific T cell tolerance via antigen presentation. It is well accepted that LSEC damage would be caused by PH due to imbalance of portal flow in SFSGs. Therefore, we hypothesized that the tolerogeneic property of LSECs would be impaired in SFSGs and could be restored by attenuating PH.

In this study, we used 70% hepatectomized mice models with or without (w/o) portosystemic shunts (PSS) to investigate the immune status of the liver in SFSGs and effect of PH, especially on LSECs.

Methods:

On day -28, the PSS were performed in female Balb/c mice; day 0, 70% hepatectomies were performed on the Balb/c mice; and day 3, anti-donor reaction were evaluated using mixed hepatic constituent cells-lymphocyte reaction (MHLR) assay. In this assay, whole hepatic constituent cells (HCs) were isolated from the livers of untreated or hepatectomized mice with or without (w/o) PSS, co-cultured with CFSE-labeled allogeneic B6 splenocytes for 4 days, and B6 T-cell proliferation was quantified by flow cytometry.

Further, on day 3, we performed phenotypic analysis of the LSECs and dendritic cells (DCs) in the livers of these mice.

Results:

The MHLR assay revealed that Balb/c HCs from 70% hepatectomized mice w/o PSS induced a significantly higher anti-Balb/c response of B6 T cells than that from untreated mice. However, Balb/c HCs from 70% hepatectomized mice with PSS showed a significant reduction of accelerated B6 T-cell response.

Phenotypic analysis revealed that LSECs from hepatectomized mice w/o PSS significantly downregulated their expressions of MHC class II and co-stimulation molecules (CD80 and CD86), while those from hepatectomized mice with PSS recovered expression of those molecules. The phenotype of DCs showed no significant change.

Conclusion:

The above results suggest that the immunosuppressive property of LSECs is impaired in SFSGs, resulting in an accelerated anti-donor reaction, which is restored by PSS. This implies that attenuating PH may prevent the accelerated rejection induced in SFSGs, thus, improve clinical results.

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