Long-term Clinical Relevance of De Novo Donor-Specific Antibodies After Pediatric Liver Transplantation

Grabhorn, Enke; Binder, Thomas M.C.; Obrecht, Denise; Brinkert, Florian; Lehnhardt, Anja; Herden, Uta; Peine, Sven; Nashan, Björn; Ganschow, Rainer; Briem-Richter, Andrea

doi:10.1097/tp.0000000000000638

Cited by 58 publications

(60 citation statements)

References 34 publications

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“…Class II donor‐specific human leukocyte antigen antibodies (DSAs), mostly DQ, are found in 50%‐60% of children following LT, most of which are formed de novo. Positivity has been associated with graft inflammation, fibrosis, and de novo autoimmune hepatitis.…”

Section: Detection Of Late Allograft Hepatitis and Fibrosismentioning

confidence: 99%

Late graft hepatitis and fibrosis in pediatric liver allograft recipients: Current concepts and future developments

et al. 2016

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Liver transplantation (LT) in children now has a 20-year survival of >80%, but the longterm outcome of these grafts remains uncertain. Serial protocol liver biopsies after transplantation from several pediatric centres have demonstrated the gradual development of unexplained graft inflammation ("idiopathic" posttransplant hepatitis; IPTH) and graft fibrosis in biopsies obtained >12 months post-LT in children with good graft function and (near) normal liver biochemistry. Although the clinical significance of these findings is uncertain, there is evidence to suggest that IPTH may be a form of rejection or chronic antibody-mediated rejection as it is associated with the presence of auto/alloantibodies; de novo Class II donor-specific HLA antibodies (DSA); previous episodes of rejection, and may improve or be prevented with increased immunosuppression. Currently, the only method of diagnosing either hepatitis or fibrosis has been by serial protocol biopsies as neither serum markers of fibrosis nor noninvasive methods to detect fibrosis such as transient elastography (TE) are sufficiently validated in children. This review will focus on the diagnosis and management of idiopathic posttransplant hepatitis and graft fibrosis, discuss current methods for detecting graft injury, and potential mechanisms for their development. Liver Transplantation 22 1593-1602 2016 AASLD.

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Section: Detection Of Late Allograft Hepatitis and Fibrosismentioning

confidence: 99%

Late graft hepatitis and fibrosis in pediatric liver allograft recipients: Current concepts and future developments

et al. 2016

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“…With a MFI cutoff above 1000, which has been recently accepted to define the presence of clinically relevant DSA especially in pediatric recipients, 45% of our pediatric patients were considered as positive for DSA at 10 years after transplantation. The same frequency was observed by Miyagawa‐Hayashino et al In adult liver recipients, there are few data about the DSA frequency at 10 years after transplantation, but it seems to be lower.…”

Section: Discussionmentioning

confidence: 99%

Morphological characterization of chronic antibody‐mediated rejection in ABO‐identical or ABO‐compatible pediatric liver graft recipients

et al. 2018

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This study aims to define the morphological profile associated with the presence of donor-specific antibodies (DSAs) and/or C4d immunostaining in ABO-identical or compatible pediatric liver grafts. Ten-year protocol liver graft biopsies performed at 131.3 ± 15.3 months after transplantation in 53 pediatric liver graft recipients were reviewed. Immunostaining for C4d was systematically performed and semiquantitatively analyzed. DSAs were concurrently quantified, and results were available for 44 patients. All biopsies demonstrated fibrotic changes with a mean liver allograft fibrosis score (LAFSc) of 5.1 ± 2.2. A total of 31 (58%) biopsies exhibited C4d positivity. DSAs were detected in 20 (45%) patients, and mean maximal mean fluorescence intensity was 12,977 ± 6731. LAFSc (6.3 ± 1.3 versus 3.9 ± 2.2; P = 0.008), perivenular fibrosis (2.7 ± 0.5 versus 1.3 ± 1.0; P < 0.001), and portal inflammation (1.4 ± 0.8 versus 0.3 ± 0.5; P = 0.009) were significantly higher in the double-DSA and C4d-positive group versus the double-negative group. We defined a histological scoring system from these results, which was integrated with the 2016 Banff definition and allowed reclassifying patients for the diagnosis of chronic active antibody-mediated rejection (cAMR; 11/53 versus 13/53). Diagnoses of probable cAMR according to Banff 2016 (n = 4) were unchanged, but 2 among the 9 patients classified as possible cAMR according to the 2016 Banff definition were excluded for this diagnostic when using our histological score. In conclusion, our results confirmed that perivenular fibrosis and portal inflammation in late pediatric liver graft biopsies are features of cAMR. Our histological score could improve the accuracy of the 2016 Banff definition for the diagnosis of cAMR. Liver Transplantation 24 897-907 2018 AASLD.

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“…The early reports of children maintained on standard‐of‐care IS have not correlated history of rejection and the nature of the IS regimen, including the use of corticosteroids, with the development of fibrosis. In more‐recent reports, some of which include children who have undergone IS minimization, detection of donor‐specific antibodies (DSAs) and positive staining for C4d has been associated with fibrosis, implicating a role for humoral allo‐immune responses . Finally, reinstitution of IS for those who have undergone withdrawal or intensification of IS for those maintained on standard IS each have been reported to stabilize and even reverse fibrosis, implicating insufficient IS as a potential mechanism driving chronic allograft damage …”

mentioning

confidence: 99%

“…In morerecent reports, some of which include children who have undergone IS minimization, detection of donorspecific antibodies (DSAs) and positive staining for C4d has been associated with fibrosis, implicating a role for humoral allo-immune responses. (5,(10)(11)(12) Finally, reinstitution of IS for those who have undergone withdrawal or intensification of IS for those maintained on standard IS each have been reported to stabilize and even reverse fibrosis, implicating insufficient IS as a potential mechanism driving chronic allograft damage. (6,9,13) We have conducted and reported on a prospective pilot trial of IS withdrawal for pediatric recipients of living donor liver allografts (WISP-R; NCT00320606).…”

mentioning

confidence: 99%

Five‐year histological and serological follow‐up of operationally tolerant pediatric liver transplant recipients enrolled in WISP‐R

et al. 2016

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Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). While IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606) were followed for a total of five years (one year of IS withdrawal and four years off IS) with serial liver tests, auto- and allo-antibody assessments. Liver biopsies were performed two and four years off IS and, at these time points, immunoglobulin G (IgG) subclass and C1q binding activity for donor specific antibodies (DSAs) were determined. There were no cases of chronic rejection, graft loss, or death. Allografts did not exhibit progressive increase in inflammation or fibrosis. Smooth muscle actin (SMA) expression by stellate cells and CD34 expression by liver sinusoidal endothelial cells (LSECs) remained stable, consistent with the absence of progressive graft injury. Three subjects never exhibited DSA. However, three subjects showed intermittent de novo Class I DSA, four subjects showed persistent de novo Class II DSA and five subjects showed persistent pre-existing Class II DSA. Class II DSA was predominantly against donor DQ antigens, often of high mean fluorescence intensity (MFI), rarely of the IgG3 subclass, and often capable of binding C1q. Conclusion Operationally tolerant pediatric liver transplant recipients maintain generally stable allograft histology in spite of apparently active humoral allo-immune responses. The absence of increased inflammation or progressive fibrosis suggests that a subset of liver allografts seem resistant to the chronic injury that is characteristic of antibody-mediated damage.

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Long-term Clinical Relevance of De Novo Donor-Specific Antibodies After Pediatric Liver Transplantation

Cited by 58 publications

References 34 publications

Late graft hepatitis and fibrosis in pediatric liver allograft recipients: Current concepts and future developments

Late graft hepatitis and fibrosis in pediatric liver allograft recipients: Current concepts and future developments

Morphological characterization of chronic antibody‐mediated rejection in ABO‐identical or ABO‐compatible pediatric liver graft recipients

Five‐year histological and serological follow‐up of operationally tolerant pediatric liver transplant recipients enrolled in WISP‐R

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