De Novo Donor-Specific HLA Antibody Formation in Two Patients With Crigler-Najjar Syndrome Type I Following Human Hepatocyte Transplantation With Partial Hepatectomy Preconditioning

Abstract

Clinical hepatocyte transplantation is hampered by low engraftment rates and gradual loss of function resulting in incomplete correction of the underlying disease. Preconditioning with partial hepatectomy improves engraftment in animal studies. Our aim was to study safety and efficacy of partial hepatectomy preconditioning in clinical hepatocyte transplantation. Two patients with Crigler‐Najjar syndrome type I underwent liver resection followed by hepatocyte transplantation. A transient increase of hepatocyte growth factor was seen, suggesting that this procedure provides a regenerative stimulus. Serum bilirubin was decreased by 50%, and presence of bilirubin glucuronides in bile confirmed graft function in both cases; however, graft function was lost due to discontinuation of immunosuppressive therapy in one patient. In the other patient, serum bilirubin gradually increased to pretransplant concentrations after ≈600 days. In both cases, loss of graft function was temporally associated with emergence of human leukocyte antigen donor‐specific antibodies (DSAs). In conclusion, partial hepatectomy in combination with hepatocyte transplantation was safe and induced a robust release of hepatocyte growth factor, but its efficacy on hepatocyte engraftment needs to be evaluated with additional studies. To our knowledge, this study provides the first description of de novo DSAs after hepatocyte transplantation associated with graft loss.

Unique CD8+ T Cell–Mediated Immune Responses Primed in the Liver

“…Clinical experience to date with hepatocyte or islet transplant to the liver demonstrate the failure to achieve long-term cellular allograft survival despite the use of conventional immunosuppression. Thus, in contrast to the immunotolerant theory of the liver microenvironment which would predict the need for minimal immunosuppression, the current studies highlight the need to develop more effective immunotherapeutic strategies to target both unique CD8-mediated immune responses primed in the liver and conventional alloimmune rejection pathways 13,17,18,71 .…”

mTOR Inhibition Suppresses Posttransplant Alloantibody Production Through Direct Inhibition of Alloprimed B Cells and Sparing of CD8+ Antibody-Suppressing T cells

“…Given the importance of AMR in causing acute graft dysfunction 11 and the negative correlation of DSA with long-term allograft survival for both cell and organ transplants 7-9,35-38 , it is of great interest to devise optimal maintenance immunosuppression to suppress the emergence of DSA posttransplant. The clinical literature includes publications which report that no current immunosuppressive regimens effectively prevent the development of DSA 10,11 , while others infer relative efficacy of CNi by reporting that conversion of kidney transplant recipients from CNi to mTORi-based therapy is associated with a negative impact on DSA production and graft survival 19,39-41 .…”

“…CNi-based immunotherapies are used following clinical cell transplantation including hepatocyte transplantation but have been associated with limited success for sustained hepatocellular allograft survival 9,58-60 While early studies have not sufficiently explored alloantibody responses following clinical hepatocyte transplant, recently Jorns et al reported the development of de novo donor-specific HLA antibody in 2 patients who underwent hepatocyte transplantation. The onset of humoral alloimmunity and graft loss occurred in the context of lowering and eventual discontinuation of immunosuppression in 1 patient and despite the use of maintenance immunosuppression with CNi and low dose steroids in the second case 9 . The current experimental studies which demonstrate the lack of efficacy of CNi for suppression of alloantibody production provide insight into clinical studies which demonstrate detection of DSA in CNi-treated recipients.…”

“…De novo DSA are particularly detrimental to cellular transplants, which have relatively smaller parenchymal cell mass and increased exposure to circulating antibodies 5 . Development of humoral alloimmunity after islet 6-8 and hepatocyte transplant 9 is associated with deterioration of graft function and is a barrier to long-term graft survival. Current therapies available for treatment of AMR include removal of deleterious alloantibodies, targeting IgG + cells, cellular depletion, or a combination of these strategies 10,11 .…”

Clinical Hepatocyte Transplantation: What Is Next?

“…The development and contribution of donor-specific antibodies (DSA) in HT is still very much unknown. The presence of de novo DSA following HT has been temporarily associated with graft loss (9, 25) and in one reported case was associated with the peak measurement of the immune reactivity index score that has been shown to enable the prediction rejection (25). Ultimately, a more robust understanding of the immunological responses induced by HT is needed to help guide therapeutic regimens that will enable extended cell graft survival and broader application of HT to patients who will benefit from this promising therapy.…”