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The biomarker, class I human leukocyte antigen (HLA) evolutionary divergence (HED), was tied to liver transplant rejection in adults and children, French researchers found.

In a retrospective study, adult-donor class I HED was associated with acute liver transplant rejection (HR 1.09, 95% CI 1.03-1.16) and chronic rejection (HR 1.20, 95% CI 1.10-1.31), in addition to 50% or greater ductopenia (HR 1.33, 95% CI 1.09-1.62), reported Cyrille Feray, MD, PhD, of the Hôpital Paul-Brousse in Villejuif, France, and colleagues.

Child-donor class I HED was associated with acute liver transplant rejection (HR 1.16, 95% CI 1.03-1.30) regardless of the presence of donor-specific anti-HLA antibodies, the group wrote in .

"HED is an intrinsic metric of diversity at the HLA peptide complex for each person," the authors explained. "Our data suggest that the more divergent the HLA class I molecules of the donor are, the more diverse the graft derived peptides they present to the recipient's cytotoxic T cells are, and the higher the risk for rejection."

The fact that donor HLA divergence was more important than recipient HLA divergence was surprising, Feray told 乌鸦传媒. "Donor HLA divergence is stronger as a predictor than the classical HLA compatibility," he said.

"While still in an experimental phase, interesting findings such as those presented [here] may potentiate a patient-centered approach to liver transplantation and extend exciting research findings from cancer biology to solid-organ transplant," said Andrew Talal, MD, MPH, of the University at Buffalo in New York, who was not involved with the research.

End-stage liver disease requires transplantation, and recipient graft rejection occurs from recipient T-cell and B-cell interactions responding to donor HLAs, the authors said.

"Liver lesions in rejection are generated by recipients' cytotoxic T cells," Talal told 乌鸦传媒.

HLA antibodies form after immune system exposure from transplanted 'foreign' HLA, but class I (HLA-A and HLA-B) HED could help select the optimal transplant donor, Feray and colleagues explained.

Researchers analyzed national liver transplant database results from two hospitals, one for 1,154 adult patients, another for 113 children. Patients had their liver transplant from January 2004 to January 2018. Adults had donor HLA typing and post-transplant liver biopsy data available, while children had available histologic follow-up data.

They assessed liver transplant rejection due to donor or recipient HED. After transplantation, adults underwent liver biopsies at 1, 2, 5, and 10 years, while children underwent them at 1, 5, and 10 years, assessing for dysfunction. Grantham score, measuring physicochemical distance between amino acids for class I and II alleles, was used to calculate HED.

Feray and colleagues used the to diagnose liver rejection. Acute rejection was assessed by the Banff Rejection Activity Index and inflammation. Chronic rejection was measured by ductopenia, hepatic venules fibrosis, and bile duct dystrophy.

Median participant age was 53 for adults and around age 2 years for children. Two-thirds of the adults were men, while a little less than 60% of children were boys. There were 65 adults given a re-transplant (15 of whom died), and 248 died without a re-transplant. Median follow-up was 1,464 days in adults and for children, 1,668 days.

In adults, survival rates were 93% and 80% at 1 and 5 years, respectively, while graft survival rates were 92% and 76%.

After transplant, acute rejection occurred in 22% of adults, with a median time of 33 days after transplant. Chronic rejection occurred in about 8%, with a median time of 746 days after transplant. Average number of biopsies for adults was about 3.

Acute rejection occurred in 56% of children, while 54% were diagnosed with liver fibrosis.

"Transplant centers could seek to minimize donors with high HED values in recipients at high-risk for rejection" Talal said. "HED could also be considered as a personalized approach to optimize immune suppression."

Feray said he plans to research whether or not the findings hold true for other transplanted organs. "HLA divergence has been (very recently) shown to be important during bone marrow transplantation," he said.

Limitations of this study included recording donor-specific anti-HLA antibodies exclusively for children, the authors acknowledged.

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