Host conditioning and rejection monitoring in hepatocyte transplantation in humans

Abstract

Background Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Methods Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T-cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. Results Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27-year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343 ± 48μM (normal 30-119μM) to 854 ± 25μM (treatment goal ≤360μM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900 μM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. Conclusions Radiation preconditioning and serial rejection-risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure.

Clinical Hepatocyte Transplantation: What Is Next?

“…To address the problem of cellular engraftment and repopulation of donor hepatocytes after cell transplantation, liver-directed radiation has been suggested as an alternative to facilitate cellular repopulation by inhibiting host hepatocyte proliferation and inducing postmitotic hepatocyte death, allowing donor hepatocytes to preferentially proliferate and repopulate the irradiated host liver (25). The timing of radiation preconditioning of the recipient liver related to HT can also affect engraftment.…”

“…The timing of radiation preconditioning of the recipient liver related to HT can also affect engraftment. Delaying HT by 24 hours after preparative hepatic irradiation in mice was shown to enhance engraftment (72) and a shortened interval from irradiation to cell transplant resulted in a lower than anticipated engraftment rate in human studies (25). …”

“…Here, HT aims to temporarily improve liver function and allow the natural regenerative capacity of the liver to proceed or to stabilize and bridge affected patients to more traditional liver transplant. Indeed, published experiences of HT in the treatment of liver-based metabolic diseases (2–16) and ALF (17–21) have shown promising early results; however, only partial correction of metabolic disorders has been achieved and HT has not shown to reliably circumvent the need for traditional organ transplant in ALF (5, 6, 8, 12, 14, 21–25). Thus, in many ways HT has yet to live up to its expectations.…”

“…(Table 1) A recent review of the clinical outcomes of the first 100 patients treated with HT has been published (30) and an additional 43 patient experiences have been reported (26). While a detailed clinical report is beyond the scope of this article, it is noted that significant barriers persist limiting broader HT implementation (26, 31, 32) explicitly highlighted in a recent report that included a preclinical and clinical approach (25). The identification of these impediments has led to recent advancements looking to overcome the limitations.…”

Phenylketonuria felnőttkorban

“…Sikeres állatkísérleteket követően az első humán vizsgálatot 2016-ban zárták le [47]. A beavatkozás minimális invazivitással járt, és potenciálisan ismételhető, így alkalmas lehet azon betegek kezelésére, akiknél a mentális érin-tettség miatt a diéta tartósan nem betartható [48].…”