Presence of Autoantibody Against ATTR Val30 Met After Sequential Liver Transplantation. Transplantation 2002; 73: 751. (2002)

TRANSTHYRETIN AMYLOIDOSIS: OPTIONS AND HOPES In this issue of Transplantation, Yukio Ando and colleagues report the finding of antibodies directed against mutated transthyretin (TTR) in patients who received variant TTR-producing livers (1). And importantly, the presence of the antibody was accompanied by a reduction of circulating variant TTR in the blood. This finding raises several important questions: what impact has a reduction of mutated amyloidogenic TTR (ATTR) on the development of amyloidosis in variant TTR liver recipients? And even more interesting, could antibodies be used in the treatment of TTR amyloidosis or prevent the development of the disease in carriers of the trait? Although an assembly of wild-type TTR into amyloid causes senile amyloidosis, early onset TTR amyloidosis is caused by mutated TTR. More than 70 different amyloidogenic mutations are described in the literature, of which the patients that are the most common candidates for liver transplantation carry a point mutation at position 30 (ATTR Val30 Met). This mutation gives rise to a predominantly neuropathic amyloidosis: familial amyloidotic polyneuropathy (FAP), Portuguese-type. From population studies, it has been shown that asymptomatic carriers of the mutation are common and that the phenotype and age of onset (33–56 years) varies considerably between different populations (2) In the paper by Ando et al. (1), a reduction of circulating variant TTR throughout the study period was observed, with a ratio of variant to wild-type TTR of 0.3 to 0.4, a considerable reduction of the variant form. It appears reasonable to expect that a reduction of the amyloidogenic variant TTR in the circulation should decrease the chance to develop amyloidosis in the recipients of the ATTR Val30 Met-producing livers. However, for homozygous patients, the onset and progress of disease is similar to that of heterozygous patients, and asymptomatic homozygous carriers of the trait exist. Moreover, most of the Swedish carriers of the trait are asymptomatic (2). Thus, no relationship has been proven between concentration of variant TTR and development of disease. Interestingly, x-ray analysis of the ATTR Val30 Met mutation shows no conformational changes compared to the wild-type TTR. However, conformational changes of TTR appear to be necessary for amyloid fibril formation. Recently, a monoclonal antibody has been developed that recognizes cryptic epitopes shared by several ATTR variants associated with TTR amyloidosis, and these epitopes were not present among nonpathogenic TTR molecules (3). The importance of the paper by Ando et al. (1) lies in the finding that recipients of variant TTR livers develop antibodies directed towards variant TTR. It would be interesting to know whether these antibodies recognize epitopes that comprise the change in the primary structure or a conformational change somewhere in the molecule. What about treatment of FAP patients and carriers with antibodies to reduce or to eliminate variant TTR from the circulation? It is already established in a mouse model that the immune system may cope with the pathological effects of amyloidogenic proteins (4). From our experience of liver transplantation for patients who carry the ATTR Val30 Met mutation, it is obvious that the procedure halts the production of circulating variant TTR and, in principle, stops amyloid formation and further progress of the disease (2). Thus, if we can eliminate variant TTR, we should prevent disease in carriers and halt progress in FAP patients. Antibodies directed against TTR have previously been used in the treatment of TTR amyloidosis in a technically demanding intermittent procedure. However, the effect has not been convincing possibly because of factors such as turnover and de novo synthesis of TTR. From the paper by Ando et al. (1), it appears that a sustained reduction of variant TTR concentration in the plasma can only be achieved by a steady presence of antivariant TTR antibodies, i.e., daily or continuous plasmapheresis or antibody administration. Recently, a conformational change was described of an unstable and extremely amyloidogenic triple mutant of TTR, which exposed a cryptic epitope not expressed in wild-type TTR. The epitope could be recognized by mouse monoclonal antibodies, which were conformation dependent (5). Occasionally, normal individuals do express antibodies with the same epitope specificity (A. Olofsson and E. Lundgren, unpublished data, 2000). Antibodies directed towards such cryptic epitopes expressed in unstable amyloidogenic TTR molecules may be advantageous for treatment of TTR-associated amyloidosis. Thus, several possible targets for anti-TTR amyloid antibodies exist, either directed against the primary structure caused by the mutation or against an amyloidogenic conformational change somewhere in the molecule. What are today’s options for FAP patients? Liver transplantation appears for now to be the only treatment of choice. The transplantation should be performed during the early phases of the disease, because organ damage appears to be irreversible and the mortality and morbidity for patients transplanted in later stages of the disease are unacceptably high (2). This means that patients should be transplanted while they still exhibit only mild or moderate dysfunction from the disease. This is a problem in the priority of patients on the waiting list for transplantation where amyloid patients in good condition must compete with patients with severe liver disease. The sequential liver transplantation procedure, initially suggested and performed by Prof. Furtado in the Universidad de Quimbara, Portugal, has to some extent diminished the problem. In most countries, TTR amyloidosis is a minor problem. But in Portugal and Japan and probably also Brazil, where large endemic foci of the disease are found and where the majority of the patients get the disease in their thirties, patients with FAP are one of the largest groups of patients in need of a liver transplantation. The paper by Ando et al. points to a possible treatment modality using antibodies against variant TTR, a possibility that deserves to be followed up. An elimination of variant TTR or its amyloidogenic precursors by specific antibodies should prevent carriers from developing the disease and halt progress in already affected patients.