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Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator

Year: 2019

Type: article

Abstract: Hepatocyte transplantation (HT) is a promising alternative to orthotopic liver transplantation (OLT) in paediatric patients with liver-based metabolic disorders [ 1 , 2 , 3 ]. The technique can be used as a bridge to organ transplantation or for effective long-term repopulation of the native liver, avoiding the need for liver transplantation. Liver transplantation is curative for certain liver-based metabolic disorders such as Crigler–Najjar syndrome (CNS), ornithine transcarbamylase (OTC) deficiency and maple syrup urine disease (MSUD); however, organs of suitable size and quality are rarely available at the time when the infant has the greatest need. These disorders, untreated, result in irreversible, neurological insult secondary to build up of toxic metabolic compounds as a consequence of a single enzyme deficiency. For example, in the case of neonatal onset ornithine transcarbamylase deficiency (OTC), the infant will suffer the effects of hyperammonaemia usually in the first few weeks of life and both appropriately sized organ availability and metabolic instability may preclude liver transplantation. Hepatocyte transplantation offers an immediately available and relatively less invasive alternative. The technique has shown a reduction in serum bilirubin by up to 50% in patients with CNS and a decrease in ammonia and an increase in urea production in patients with urea cycle defects [ 4 , 5 , 6 , 7 ]. However, despite numerous clinical cases reported, long-term clinical outcomes of hepatocyte transplantation have yet to be established with any type of liver-based metabolic disease. Poor long-term efficacy may be partly due to insufficient number of hepatocytes reaching the liver cell plates and significant cell loss has been observed within the first 24 h post transplantation, leading to poor engraftment and long-term cell function [ 8 ]. This has been attributed to an inflammatory reaction now commonly referred to as the instant blood-mediated inflammatory reaction (IBMIR), in which cells are recognised by the innate immune system, leading to rapid activation of both complement and coagulation pathways [ 9 , 10 ]. Additionally, inflammatory cells including granulocytes, monocytes, Kupffer cells and natural killer (NK) cells are activated leading to rapid clearance and death of transplanted hepatocytes [ 11 ]. Alpha-1 antitrypsin (AAT) is a 52-kDa, 394 amino acid serine protease inhibitor produced by hepatocytes in the liver that inhibits a wide range of proteases including neutrophil elastase [ 12 , 13 ]. AAT is a natural immune modulator with studies showing its anti-inflammatory and anti-apoptotic effects independent of protease inhibition [ 13 , 14 ]. AAT directly affects the innate immune system through inhibition of protease-activated receptors (PARs), which leads to the inhibition of pro-inflammatory signalling cascades and cytokine release. Inflammatory cell recruitment is decreased, which further dampens the innate immune response [ 15 ]. Several animal studies have demonstrated the efficacy of AAT in improving islet graft survival and function [ 16 , 17 , 18 ]. In a similar manner to hepatocyte transplantation, islets are injected into the liver to provide continuing production of insulin for type 1 diabetic patients. Long-term efficacy and function of islet transplantation has yet to be demonstrated due to loss of graft function caused by activation of the IBMIR. A multi-centre review of autologous islet transplantation showed that 31% of islets lost function within 7 days and 50% of those that survived lost all function within a year [ 19 ]. In a syngeneic non-autoimmune islet graft mouse model, 2 mg of AAT per mouse, intravenously infused, maintained euglycaemia in 75% of recipients, compared to 20–27% in the controls. Furthermore, long-term function was demonstrated in a cynomolgus monkey islet transplantation model, in which AAT improved graft survival and function for up to 700 days post transplantation, compared to control monkeys in which blood glucose and C-peptide levels rose after just 80 days [ 18 ]. There are now several clinical trials in progress testing the use of AAT in the context of islet transplantation [ 20 ].

Source: Journal of Molecular Medicine

DOI: 10.1007/s00109-019-01747-3