Alpha-1 antitrypsin to improve the efficacy of hepatocyte transplantation in children with liver-based metabolic disease

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Hepatocyte (Liver cell) transplantation is an alternative to liver transplantation for certain conditions. It involves the transplantation of the cells into the patient's liver, usually via the main vein supplying the liver, in a minimally invasive way. Patients for whom this treatment is especially suitable are those who are missing a particular enzyme which is made in the liver cell. This leads to buildup of toxic waste products and consequent irreversible brain injury. Two such conditions: Crigler-Najjar syndrome (where bilirubin cannot be broken down), and the urea cycle defects (where ammonia is not eliminated), cause profound brain injury due to accumulation of these toxic compounds. Replacing the whole liver, to replace the missing enzyme, is an option but comes at a high price as this involves major surgery, often with complications, a prolonged hospital stay, and leaves no fallback if the transplant fails. Furthermore, the donor organ pool is particularly small for children, who will need part of an adult liver. Thus the wait for a suitable organ may be years for children who have an extremely poor quality of life and with the potential to develop a metabolic 'crisis' at any point in time. In addition, they only actually need a fraction of liver in order to correct the deficiency. There is thus a redundancy in replacing a whole liver, particularly in view of the restricted resource and large demand. Hepatocytes are isolated from livers that don't meet the criteria for organ transplantation, and so they are an excellent use of an otherwise unusable resource. They can be frozen and stored and thus are available off the shelf. Hepatocyte transplantation also allows the patients own liver to be preserved while providing 10-15% of the liver function, i.e. sufficient function from the otherwise deficient enzyme to correct the disease. We know that, at time of infusion into the portal vein, the cells encounter attack from the innate immune system: blood begins to clot, proteins are released, attracting the defence cells of the body, and hepatocytes are destroyed before they can reach the liver to engraft and settle. Conventional immuno-suppression including steroids doesn't allow to overcome this and so, more than ninety percent of cells are destroyed before they have the opportunity to engraft. Alpha-1 antitrypsin (AAT) is a protein made in liver cells and has a range of effects which can block a lot of the adverse effects of inflammation without the side effects of most conventional immunosuppressants, which leave the body vulnerable to attack from infection and cause poor wound healing. AAT is used in clinical trials world-wide, in a variety of conditions which are influenced by inflammation such as type 1 diabetes and ischaemic heart disease. Considerable success of AAT as an immune system modifier has also been seen in the field of islet transplantation in patients with diabetes, where these insulin producing cells are also transplanted into the liver. We wish to test the use of AAT in the field of hepatocyte transplantation as we believe that it will lead to improved engraftment of cells in the liver and thus, better medium- to long-term function of the cells, making a significant difference to those treated. We predict that the mechanism through which this occurs will be the suppression of the innate (immediate) immune system and we will measure both the function of the cells in terms of supplying the missing enzyme as well as the effect that AAT has on the immediate immune response once these cells are infused. Though hepatocyte transplantation is a small field, it can result in life-changing treatment for children with devastating liver-based disease. Should we demonstrate the success of this therapy using AAT, this will give further credence to the use of AAT as an effective and safe immuno-modulator, in the context of transplantation in general, and in other inflammatory conditions.