Mammalian models of extended healthy lifespan

Over the last two centuries, there has been a significant increase in average lifespan expectancy in the developed world. One unambiguous clinical implication of getting older is the risk of experiencing age-related diseases including various cancers, dementia, type-2 diabetes, cataracts and osteoporosis. Historically, the ageing process and its consequences were thought to be intractable. However, over the last two decades or so, a wealth of empirical data has been generated which demonstrates that longevity in model organisms can be extended through the manipulation of individual genes. In particular, many pathological conditions associated with the ageing process in model organisms, and importantly conserved from nematodes to humans, are attenuated in long-lived genetic mutants. For example, several long-lived genetic mouse models show attenuation in age-related cognitive decline, adiposity, cancer and glucose intolerance. Therefore, these long-lived mice enjoy a longer period without suffering the various sequelae of ageing. The greatest challenge in the biology of ageing is to now identify the mechanisms underlying increased healthy lifespan in these model organisms. Given that the elderly are making up an increasingly greater proportion of society, this focused approach in model organisms should help identify tractable interventions that can ultimately be translated to humans

ALLOREACTIVE T LYMPHOCYTES CULTURED FROM LIVER TRANSPLANT BIOPSIES: ASSOCIATIONS OF HLA SPECIFICITY WITH CLINICOPATHOLOGICAL FINDINGS.

Lymphocyte cultures grown from liver allograft biopsies were shown to exhibit alloreactivity towards donor cells as measured by primed lymphocyte testing (PLT). The PLT specificity was determined in assays using HLA typed panel cells and/or by inhibition testing with HLA specific monoclonal antibodies. Certain cultures exhibited PLT specificity towards class I HLA antigens of the donor, whereas others were specific for class II HLA antigens or recognized mixtures of class I and II antigens. These PLT specificity patterns were compared with clinical, histological and laboratory findings on the liver transplant patients at the time of the biopsy. Biopsies yielding class I specific PLT cells were taken generally during the earlier posttransplant period, whereas class II specific cells were grown from later biopsies. There was no significant correlation of the PLT specificity towards class I vs II antigens with the levels of total or direct bilirubin, serum glutamate oxaloacetic transaminase (SGOT), and serum glutamate pyruvate transaminase (SGPT), although a trend towards higher values was noted for biopsies presenting with a class II specific infiltrate. However, the levels of gamma glutamyl transpeptidase (GGTP) and alkaline phosphatase (AP) were significantly increased when biopsies yielded class II specific rather than class I specific PLT cells. Biopsy histology showed more damage to bile duct epithelium in association with class II PLT specificity whereas intense but often reversible infiltrates were found in biopsies yielding class I specific cells. The elevated GGTP and AP levels are probably related to the interaction of class II specific T cells with bile duct epithelium, which has been shown to express induced class II HLA antigens on their cell surface

Combined liver-kidney transplantation: Analysis of patients with preformed lymphocytotoxic antibody

In this report, we address combined liver-kidney transplantation, with particular attention to the apparent phenomenon of protection of kidney allografts to antibody mediated destruction by liver allografts. Four patients were found to have positive crossmatch before the liver phase of the combined transplant (pre-OT/KT samples). These positive crossmatches were due entirely to anti-HLA class I antibodies, as demonstrated by their removal by immunoabsorption on pololed platelets. In three of these patients, post-OT/pre-KT samples showed a conversion to a negative crossmatch (in the fourth patient this was not done). A kidney allograft, harveted from the same donor, was then placed into the recipient, and in patients no. 3, 7, and 12, good initial function was noted. In one of these patients was there evidence of hyperacute rejection. Post-OT/KT samples were collected in patients no. 3, 7, and 8, and then analyzed for the reappearance of donor specific lymphocytotoxic antibodies in the posttransplant period (data on patient no. 12 was not available at time of preparation). Lymphocytotoxic antibodies with donor specificity could not be detected in any of the samples during the first week posttransplant. The decrease in %PRA and conversion of a positive to negative crossmatch following liver transplantation was correlated to the HLA specificty of the antibody found in the pretransplant serum and the HLA type of the tranplanted organs. In the two instances where an HLA specificity could be determined by panel analysis, transplantation with donor organs bearing these HLA specificities led to a specific disppearance of these antibodies during the postransplant phase

Isolation and primary cultures of human intrahepatic bile ductular epithelium

A technique for the isolation of human intrahepatic bile ductular epithelium, and the establishment of primary cultures using a serum- and growth-factor-supplemented medium combined with a connective tissue substrata is described. Initial cell isolates and monolayer cultures display phenotypic characteristics of biliary epithelial cells (low molecular weight prekeratin positive; albumin, alphafetoprotein, and Factor VIII-related antigen negative). Ultrastructural features of the cultured cells show cell polarization with surface microvilli, numerous interepithelial junctional complexes and cytoplasmic intermediate prekeratin filaments. © 1988 Tissue Culture Association, Inc