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

Abstract

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.

IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients

“…Patients with detectable class II DSA, compared to those without, had a higher median (interquartile range) total class II eplet mismatch (33 vs 26 ) and HLA-DQ alone mismatch (12 [8][9][10][11][12][13][14][15][16] vs 8 [4][5][6][7][8][9][10][11][12][13][14][15]). Patients with detectable class II DSA, compared to those without, had a higher median (interquartile range) total class II eplet mismatch (33 vs 26 ) and HLA-DQ alone mismatch (12 [8][9][10][11][12][13][14][15][16] vs 8 [4][5][6][7][8][9][10][11][12][13][14][15]).…”

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

“…Yet chronic rejection is an infrequent reason for allograft loss following LT, affecting only 3-4% of liver allografts among adult recipients maintained on tacrolimus-based immunotherapy [33]. Furthermore, results from immunosuppression withdrawal trials in pediatric LT recipients indicate that even operationally tolerant patients may harbor DSA, and the mere presence of DSA does not necessarily correlate with progressive increase in histologic inflammation or fibrosis [34]. …”

Longterm outcome of the liver graft: The pathologist's perspective

“…Considerable attention has been placed on structural integrity of liver allografts (especially pediatric) because of expectation of decades of morbidity‐free survival . Most studies in pediatric recipients, where primary disease recurrence is not a significant issue, show a high (>40%) incidence of histopathologically significant inflammation and progressive fibrosis by 5‐10 years after transplantation .…”

“…Instead, a majority of deaths are associated complications of immunosuppression, which can interact with adverse consequences of “normal aging.” This fact highlights a need for balancing chronic immunosuppression that prevents allo‐immunological injury (protection of the allograft) with protection of the patient from adverse consequences of chronic immunosuppression (eg, cardiovascular disease, hypertension, diabetes, renal disease, malignancies). Ideally, a choice “between Scylla and Charybdis” (protecting the graft versus protecting the recipient) might be mitigated by the study of spontaneous liver allograft tolerance, which has recently shed light on potential causes of liver allograft injury and who might benefit from immunosuppression lowering . The ultimate goal is to develop a personalized algorithmic longterm follow‐up plan that titrates immunosuppression based on a balance between graft versus overall patient health.…”

“…The major advantages of histopathological analysis, which cannot be currently obtained from other approaches, include deconvolution at a cellular level or preservation of spatial and temporal relationships among various cell types, which is critical to understanding underlying pathophysiological mechanisms. This is particularly true for liver allograft biopsies where the compartmentally localizing various changes have enabled us to uncover underlying mechanisms of tissue injury, such as localization of complement component 4d (C4d) binding to portal capillaries with human leukocyte antigen (HLA) DSA and sinusoids in non‐HLA DSA (eg, anti‐angiotension receptor type 1 antibodies [AT1R]) …”