Donor-specific HLA Antibodies Are Associated With Late Allograft Dysfunction After Pediatric Liver Transplantation

Abstract

Background The role of donor-specific HLA antibodies (DSA) following pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes. Methods Serum samples were collected at routine clinic visits from fifty pediatric LTx recipients classified into three clinical phenotypes: non-tolerant (n=18) with de-novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n=25) on maintenance tacrolimus; operationally tolerant (n=7). Samples were blinded and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA. Results DSA were detected in 54% (n=27) of patients, with the majority directed at HLA class II antigens (41% DR, 53% DQ). Patients with DSA were younger at time of LTx (p=0.016) and time of study (p=0.024). Mean AST, ALT, total bilirubin, and GGT were higher in DSA positive patients, though did not reach statistical significance. Non-tolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (p=0.021). The non-tolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (p=0.015) and 8.6 (p=0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (p=0.004) and 10.8 (p=0.006), respectively. Conclusions Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection.

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

“…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 …”

The Role of Humoral Alloreactivity in Liver Transplantation: Lessons Learned and New Perspectives

“…These mechanisms, however, do not confer complete protection against allospecific HLA antibodies; LT recipients who develop de novo DSA demonstrate inferior survival, particularly when DSA against HLA class II antigens [12–14] and IgG3 subclass DSA [15] are present at high titers. Other reports have associated DSA with late acute rejection [16] and chronic ductopenic rejection [17]. A summary of the recent studies investigating the effects of de novo DSA on LT outcomes is presented in Table 1.…”

Production of Proinflammatory Cytokines by Monocytes in Liver-Transplanted Recipients with De Novo Autoimmune Hepatitis Is Enhanced and Induces TH1-like Regulatory T Cells

“…An important cause of late allograft dysfunction is de novo autoimmune hepatitis (dAIH). The etiology and underlying pathogenesis of de novo autoimmune remains unclear and while several risk factors such as preceding acute rejection episodes, steroid dependence (1), human lymphocyte antigen phenotype (2, 3), gender and age of the organ donor (4), have been reported and mechanisms proposed to explain the immune response observed (5-9), importantly, these risk factors have not been consistently observed in all patients.…”