Clinical relevance of donor specific human leukocyte antigen antibodies after pediatric liver transplantation
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EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 867, 2021
Clinical relevance of donor‑specific human leukocyte
antigen antibodies after pediatric liver transplantation
WEI LIU1, KAI WANG2, YAN‑LI XIAO1, CHUN LIU1, WEI GAO2 and DAI‑HONG LI1
Departments of 1Blood Transfusion and 2Transplantation Surgery,
Tianjin First Central Hospital, Tianjin 300192, P.R. China
Received September 3, 2019; Accepted September 30, 2020
DOI: 10.3892/etm.2021.10299
Abstract. Donor‑specific human leukocyte antigen (HLA) Introduction
antibodies (DSAs) have a significant role in graft survival
after pediatric liver transplantation. To understand the Increasing evidence has indicated that the existence of
significance of DSAs, a retrospective cohort study of donor‑specific human leukocyte antigen (HLA) anti-
48 pediatric liver transplant recipients with posttransplant bodies (DSAs) may adversely affect the long‑term survival
serum samples that were analyzed for DSAs was performed. of grafts (1). DSAs in kidney and heart transplant recipients
According to their test results, the recipients were divided have been associated with acute T‑cell‑mediated rejection,
into a DSA‑positive group and a DSA‑negative group. antibody‑mediated rejection (AMR), progression to chronic
Postoperative liver transplantation biopsies were performed rejection, late graft dysfunction, vasculopathy and allograft
in patients with abnormal liver function. The liver condition loss (2‑6).
and prognosis of the recipients were recorded, and their In adult liver transplantation, the effect of DSAs on
association was analyzed. A total of 48 recipients were long‑term survival is controversial, but DSAs may be a risk
followed up for 2.7±0.8 years. DSA positivity was detected factor for poor survival (7‑9). Patients undergoing liver trans-
in 10 cases (20.8%). One case was positive for HLA class I plantation with preformed DSAs have been indicated to be at
and HLA class II antibodies, whereas 9 cases were positive increased risk of hyperacute rejection (10) and AMR within
for HLA class II antibodies, and the gene loci were HLA‑DR the first weeks after transplantation (11‑13). In addition, DSAs
and/or DQ. Antibody‑mediated rejection (AMR) occurred in have been associated with chronic rejection (14,15), acceler-
four of 10 patients in the DSA‑positive group. Liver function ated fibrosis (16,17) and anastomotic biliary strictures (18).
was abnormal in 3 of 38 cases in the DSA‑negative group. Compared with adult recipients, pediatric liver transplant
Multivariate analysis revealed that DSA positivity was an recipients exhibit a higher incidence of DSAs after liver trans-
independent risk factor for liver insufficiency and long‑term plantation. It has been reported that the positive rate of DSAs in
survival of recipients. In addition, Kaplan‑Meier survival pediatric liver transplant recipients can be as high as 54% (19).
analysis demonstrated that there were significant differences However, the relationship between the presence of DSAs and
in the survival of graft recipients between the DSA‑positive AMR after pediatric liver transplantation and how it affects the
group and the DSA‑negative group (P
2 LIU et al: DONOR-SPECIFIC HLA ANTIBODIES AFTER PEDIATRIC LIVER TRANSPLANTATION
basiliximab were also used to treat patients following pediatric Table I. Characteristics of pediatric liver transplant recipients
liver transplantations; basiliximab was given on the fourth day (n=48).
post‑operatively. Sequential treatment with methylprednisolone
was administered post‑operatively and stopped at 6 months. Characteristics Data at transplantation
Tacrolimus was administered on the second day after liver
transplantation, and the trough concentration (7‑10 ng/ml) was Age, mean ± SD (range) 3.7±2.6 (1‑11)
maintained up to 3 months after pediatric liver transplanta- Sex (male/female) 27/21
tion. Following detection of DSAs, the recipients were treated Clinical diagnosis (n)
with mycophenolate mofetil (MMF; 600 mg/m2 per dose twice Biliary atresia 38
daily). Autoimmune liver cirrhosis 1
Congenital bile duct dilatation 1
Diagnostic criteria for AMR following pediatric liver Bile cirrhosis 1
transplantation. The diagnostic criteria for AMR after pedi- Alagille syndrome 1
atric liver transplantation included the following: i) early Cholestasis 6
liver transplantation insufficiency; ii) diffuse vascular endo-
thelial injury and small perivascular inflammation; iii) high Liver transplant type (n)
DSA positivity; iv) strong diffuse C4d linear staining of liver Parental transplantation 35
tissue; and v) improvement in liver function (measured using Liver transplantation after donor death 13
standard biochemical tests), decreased DSA level, improve- Blood type combination (n)
ment in liver histology (such as fibrosis and inflammation) Identical 31
and disappearance of C4d deposition after anti‑AMR Compatible 17
treatment.
HLA typing and HLA antibody determination. All patients
and donors were typed for HLA‑A, ‑B, ‑DRB1 and ‑DQB1. Roche Diagnostics) at 37˚C for 30 min, incubation with
HLA class I and II typing was performed by molecular 3,3‑diaminobenzidine at room temperature for 5 min for
methods (PCR‑sequence‑specific oligonucleotide tech- color development and hematoxylin counterstain for 30 sec
niques; One Lambda Inc.) (20). The detection of HLA (both from Roche Applied Science).
antibodies was performed using Lifecodes single‑antigen
beads class I and II (Immucor Inc.), according to the Statistical analysis. Statistical analysis was performed
manufacturer's protocol (21). Antibody results of liver using SPSS (version 20.0; IBM Corp.) and GraphPad Prism
transplantation recipients were compared with the HLA (version 5.0; GraphPad Software, Inc.) software. Continuous
of the corresponding donor to determine whether they variables are presented as the mean ± standard deviation for
were donor‑specific. The interpretation criteria for positive normally distributed data and as median (range) when the
samples were as follows: Mean fluorescence intensity (MFI) values were not normally distributed. The differences between
>10,000 was strongly positive, 4,000< MFITable II. Demographic and clinical data and specifications of patients with DSA (n=10).
Patients
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Patient characteristics 1 2 3 4 5 6 7 8 9 10
Sex (M/F) F M M F F M M M F F
Age at LT (years) 2 3 11 1 1 1 1 2 2 2
Donor age (years) 1 34 34 32 29 34 32 31 1 28
Donor type (DCD/P) DCD DCD P P P P P P DCD P
Disease type BA AS ALC BA BA BA BA BA BA BA
Amount of blood transfusions during surgery
Erythrocytes (U) 2 4 4 4 2 2 4 4 4 2
Fresh‑frozen plasma (ml) 400 400 600 400 200 200 400 400 400 200
Time post‑LT, months 7 4 1 1 1 2 4 24 12 8
AMR (Y/N) N N N Y Y Y Y N N N
Type of DSA (MFI) DQ6 DQ5 (807) DQ7 DQ7 DR7 (6,351) DQ4 A2 (2,463) DR7 (1,397) DQ7 DQ6
(18,045) DQ6 (2,573) (3,496) (15,527) DQ8 (13,707) (18,640) DR7 (18,231) DR9 (1,365) (1,894) (1,297)
DR15 (761) DQ8 (19,356)
Immunosuppression Tac Tac Tac Tac Tac Tac Tac Tac Tac Tac
Tacrolimus level in the presence of DSAs (ng/ml) 3.5 6.9 12.6 4.3 6.5 8.1 7.6 5.0 3.4 7.6
Biochemical liver test in the presence of DSAs
AST (U/l) 288.6 418 280.2 331.6 273.9 208.9 277.1 40.4 21.7 40.8
ALT (U/l) 381 317.4 232.4 307.8 237.5 160.2 301.1 50.9 35.9 48.8
EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 867, 2021
ALP (U/l) 279 382 181 463.7 231 360.3 287.5 240 331 294
Bilirubin (mg/dl) 5.4 223.7 13.38 207.2 234.8 174.9 156.4 14.9 3.5 3.58
ALC, autoimmune liver cirrhosis; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AMR, antibody‑mediated rejection; AS, Alagille syndrome; AST, aspartate aminotransferase; BA, biliary
atresia; DCD, donation after cardiac death; DSA, donor‑specific human leukocyte antigen antibodies; F, female; LT, liver transplantation; M, male; MFI, mean fluorescence intensity; N, no; Tac, tacrolimus;
Y, yes.
34 LIU et al: DONOR-SPECIFIC HLA ANTIBODIES AFTER PEDIATRIC LIVER TRANSPLANTATION Table III. Comparison of demographic and clinical parameters between pediatric transplant patient groups. Characteristics DSA group Non‑DSA group P‑value Number of patients 10 38 Sex (male/female) 5/5 22/16 0.6543 Age at LT, mean ± SD (years) 2.6±0.9 2.6±0.4 0.9961 Donor age, mean ± SD (years) 25±4.2 26±1.9 0.9321 Donor type (DCD/Parental) 3/7 10/28 0.8156 Amount of blood transfusions during surgery Erythrocytes (U) 3.2 (2‑4) 2.9 (2‑4) 0.4745 Fresh‑frozen plasma (ml) 360 (200‑400) 340 (200‑600) 0.8329 Number of transfusions, mean ± SD (n) 0.9±0.32 0.74±0.45 0.0110 Time post‑LT, mean ± SD (months) 7.4±4.5 17.5±7.8 0.0091 Acute rejection (Y/N) 6/4 3/35 0.0010 Antibody‑mediated rejection (Y/N) 4/6 0/38 0.0010 Tacrolimus level in the presence of DSA (ng/ml) 6.6±0.9 3.9±0.3 0.0005 Biochemical liver test at biopsy ALT (U/l) 227.4±46.0 43.0±7.5
EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 867, 2021 5
Figure 1. Pathological manifestations of antibody‑mediated rejection in liver allografts. (A) Hematoxylin and eosin staining. Proliferation and expansion of
small veins in the portal area, and lymphocyte and neutrophil infiltration were detected. Lymphocyte and neutrophil infiltration were also seen in the liver
sinusoid. (B) Masson staining. Fibrous tissue was observed. (C) C4d staining. C4d positive expression was detected in the venule and hepatic sinusoid in the
portal area.
against class I antigens and represented 90% of all DSAs.
The HLA-II antigen is dominated by the HLA-DQ site. It
was observed that in patients with AMR, the mean value of
HLA-DQ MFI was >15,000 and the mean value of HLA-DR
MFI was >10,000. Therefore, a high MFI value was closely
related to the occurrence of AMR. Previous research
has demonstrated that the occurrence of AMR, bile duct
complications and hepatic fibrosis in DSA-positive liver
transplantation recipients is closely related to the charac-
teristics, intensity and IgG classification of antibodies (25).
In a retrospective cohort study, such as that by Kaneku et
al (26), DSA analysis of serum samples before and after
transplantation was performed in 749 adult liver transplant
recipients. It was found that 8.1% of patients developed
DSAs 1 year after transplant. Almost all DSAs were
targeted at HLA II antigens, most of which were targeted
at HLA-DQ antigens. O’Leary and Klintmalm (27) retro-
spectively analyzed 79 children with good graft function
Figure 2. Graft recipient survival of the DSA‑positive and the DSA‑negative
group. DSA, donor‑specific human leukocyte antigen antibodies. >5 years after transplantation. The donor specificity of
antibodies was identified in 67 patients; specifically, DSAs
were detected in 32 cases (48%). The DSAs were usually
targeted at HLA class II (30 cases) and rarely against
and after plasma exchange therapy, human immunoglobulin class I (2 cases). Although the liver has the ability to absorb
(intravenous immunoglobulin, 2.5 g/day) was administered pre‑stored HLA class I antibodies, the persistence of HLA
intravenously. One patient was treated with bortezomib five class II antibodies increases the incidence of acute and
times, and the other three patients were treated with ritux- chronic rejection (27).
imab once each. During treatment, except for the routine Another finding of the present study was that DSA‑positive
daily use of MMF, other treatment methods were carried recipients exhibited abnormal liver function before AMR and
out alternately. Among the patients with AMR, only one exhibited abnormal elevation of serum transaminase, followed
case was cured after treatment, and the other three cases by hypercholanemia. O'Leary et al (28) retrospectively evalu-
finally underwent re-transplantation. ated 1,270 cases of liver transplantation and demonstrated
that immunosuppressant concentration and hormone dosage
Discussion were closely related to rejection. Another study reported
that the detection rate of DSAs in the non‑tolerant group
The liver is recognized as an immune-privileged organ (22); was 54%, mainly targeting HLA class II antigens (DR, 41%;
therefore, AMR is less common after liver transplantation DQ, 53%). The average levels of AST, ALT, total bilirubin
(23). However, the humoral immunological mechanism of and γ‑glutamyltransferase were also higher in DSA‑positive
acute rejection after liver transplantation is consistent with patients (19).
that of other organ transplantations (24). A re-evaluation of The formation of DSAs in the early stages after organ
the importance of DSAs in liver transplants was required, transplantation suggests a poor prognosis, but the pathogenesis
and the present study demonstrated a higher risk of rejection between DSAs and rejection has not been determined. In other
and decreased allograft survival in DSA-positive patients. organ transplants, such as renal, complement C4d has been
In the present study, it was observed that DSAs against recognized as a sensitive index to predict rejection; however, the
HLA class II antigens were more common than those role of C4d in liver transplantation has been controversial (29).6 LIU et al: DONOR-SPECIFIC HLA ANTIBODIES AFTER PEDIATRIC LIVER TRANSPLANTATION Although it has been reported that C4d serves an important test for all patients before transplant. Thus, the authors were role in the prediction of rejection in DSA‑positive cases, it is unable to determine whether the detected antibodies in highly specific but not highly sensitive. Some research has patients were preformed or de novo. Secondly, the sample shown that acute rejection after liver transplantation is closely size in the present study was small; more samples need to be related to the accumulation of vascular endothelial cells in collected to further analyze the relationship between DSAs the portal area. However, Ali et al (30) revealed that positive and graft loss in patients. Thirdly, the follow‑up time of staining of C4d can be found in different liver lesions, i.e., acute pediatric liver transplants needs to be extended to study the cell rejection (52%), chronic catheterization rejection (50%), 5‑year graft survival rate of children. Finally, more clinical recurrent liver disease (48%), preservation injury (18%) and data and practical experience should be accumulated in the liver necrosis (54%). Furthermore, C4d positivity was rarely diagnosis and treatment of AMR after liver transplantation found in ABO blood group‑compatible liver transplantation, in children. When the diagnosis of AMR is unknown or but it was closely related to liver fibrosis after transplant. highly suspected, liver biopsies and DSA tests should be Musat et al (15) performed liver biopsies in 43 patients with performed in a timely manner, and C4d, IgG subclass, C1q acute or chronic rejection after liver transplantation. There and C3d should be assessed at the same time (37). In conclu- was a significant positive association between C4d deposi- sion, regular monitoring of DSA levels may have an important tion and DSA intensity (MFI). The incidence of chronic role in predicting graft survival and DSA treatment choice. rejection among DQ‑DSA‑positive patients was higher than that among DQ‑DSA‑negative patients. The higher the MFI Acknowledgements value of DSAs, the higher the risk of chronic rejection. Del Bello et al (31) performed a retrospective analysis of Not applicable. 152 patients with liver transplantation and demonstrated that 21 patients (14%) developed DSAs, including 5 patients with Funding C1q‑DSA (24%) and 9 patients (43%) with AMR. The positive rate of C4d staining was higher in liver biopsies from patients The present study was supported by the Tianjin Natural Science with AMR (P
EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 867, 2021 7
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