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Distinctive protein expression in elderly livers in a Sprague-Dawley rat model of normothermic ex vivo liver machine perfusion
In: Machine Perfusion |Transplantation
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Our manuscript “Distinctive protein expression in elderly livers in a Sprague-Dawley rat model of normothermic ex vivo liver machine perfusion” has been published in the latest issue of the European Journal of Medical Research,
Authors are Maximilian Zimmer, Karl H. Hillebrandt, Nora M. Roschke, Steffen Lippert, Oliver Klein, Grit Nebrich, Joseph M.G.V. Gassner, Felix Strobl, Johann Pratschke, Felix Krenzien, Igor M. Sauer, Nathanael Raschzok, and Simon Moosburner.

Liver grafts are frequently declined due to high donor age or age mismatch with the recipient. To improve the outcome of marginal grafts, we aimed to characterize the performance of elderly vs. young liver grafts in a standardized rat model of normothermic ex vivo liver machine perfusion (NMP).

Livers from Sprague-Dawley rats aged 3 or 12 months were procured and perfused for 6 h using a rat NMP system or collected as a reference group (n = 6/group). Tissue, bile, and perfusate samples were used for biochemical, and proteomic analyses.

All livers cleared lactate during perfusion and continued to produce bile after 6 h of perfusion (614 mg/h). Peak urea levels in 12-month-old animals were higher than in younger animals. Arterial and portal venous pressure, bile production and pH did not differ between groups. Proteomic analysis identified a total of 1477 proteins with oxidoreductase and catalytic activity dominating the gene ontology analysis. Proteins such as aldehyde dehydrogenase 1A1 and 2-Hydroxyacid oxidase 2 were significantly more present in livers of older age.

Young and elderly liver grafts exhibited similar viability during NMP, though proteomic analyses indicated that older grafts are less resilient to oxidative stress. Our study is limited by the elderly animal age, which corresponds to mature but not elderly human age typically seen in marginal human livers. Nevertheless, reducing oxidative stress could be a promising therapeutic target in the future.

Tags: Publication

Quality assessment by bile composition in normothermic machine perfusion of rat livers
In: Transplantation |Machine Perfusion
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Our manuscript “Quality assessment by bile composition in normothermic machine perfusion of rat livers” has been accepted for publication in Tissue Engineering Part A.
Authors are Vanessa Muth, Felix Stobl, Julian Michelotto, Jennifer A. Kirwan, Jeremy Marchand, Nathalie N. Roschke, Simon Moosburner, Johann Pratschke, Igor M. Sauer, Nathanael Raschzok, and Joseph MGV Gassner.

Due to the persistent challenge of organ scarcity in liver transplantation, there is an escalating dependence on organs obtained from extended criteria donors (ECD). Normothermic machine perfusion (NMP) can be used for improved preservation and allows quality assessment of ECD grafts. The primary objective of this study was to assess bile composition within the framework of quality analysis and explore the impact of warm ischemia on its composition in a rodent NMP model.

30 livers from male Sprague Dawley rats were divided into five distinct groups. Each group was subjected to 6 hours of NMP using either DMEM or Steen solution as perfusate, with or without a preceding 30-minute warm ischemia period. We further examined the effect of pressure-controlled perfusion on livers experiencing 30 min WIT using Steen as perfusate. We conducted regular measurements of AST, ALT, LDH, and urea levels in the perfusate at three- hour intervals. We collected bile samples at hourly intervals and assessed biliary pH, LDH, and GGT. Bile acids were measured using mass spectrometry every two hours.

Liver injury parameters were significantly higher in our DCD model. Bile production was significantly reduced in livers exposed to warm ischemia, and the bile showed a significantly more alkaline pH. This correlated with the concentration of total bile acids, which was significantly higher in livers with 30 min WIT. Taurocholic acid and its metabolites were most prominent. Secondary bile acids were significantly reduced in the course of perfusion due to the missing enterohepatic circulation. Prolonged warm ischemia-induced liver injury affects parameters we measured in bile within our small animal NMP model. We hypothesize that this phenomenon may be attributed to the cAMP-driven nature of bile secretion, potentially explaining why DCD livers produce less, yet more concentrated, bile.

Tags: Publication

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Our manuscript "Depletion of donor dendritic cells ameliorates immunogenicity of both skin and hind limb transplants" has been accepted for publication in Frontiers in Immunology, section Alloimmunity and Transplantation. Authors are Muhammad Imtiaz Ashraf, Joerg Mengwasser, Anja Reutzel-Selke, Dietrich Polenz, Kirsten Führer, Steffen Lippert, Peter Tang, Edward Michaelis, Rusan Catar, Johann Pratschke, Christian Witzel, Igor M. Sauer, Stefan G. Tullius, and Barbara Kern.

Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA). Donor antigen presenting cells (APC), particularly dendritic cells (DC), orchestrate early alloimmune responses by activating recipient effector T cells. Employing a targeted approach, we investigated the impact of donor-derived conventional DC (cDC) and APC on the immunogenicity of skin and skin-containing VCA grafts, using mouse models of skin and hind limb transplantation.
By post-transplantation day 6, skin grafts demonstrated severe rejections, characterized by predominance of recipient CD4 T cells. In contrast, hind limb grafts showed moderate rejection, primarily infiltrated by CD8 T cells. While donor depletion of cDC and APC reduced frequencies, maturation, and activation of DC in all analysed tissues of skin transplant recipients, reduction in DC activities was only observed in the spleen of hind limb recipients. Donor cDC and APC depletion did not impact all lymphocyte compartments but significantly affected CD8 T cells and activated CD4 T in lymph nodes of skin recipients. Moreover, both donor APC and cDC depletion attenuated the Th17 immune response, evident by significantly reduced Th17 (CD4+IL-17+) cells in the spleen of skin recipients and reduced levels of IL-17E and lymphotoxin-α in the serum samples of both skin and hind limb recipients. In conclusion, our findings underscore the highly immunogenic nature of skin component in VCA. The depletion of donor APC and cDC mitigates the immunogenicity of skin grafts while exerting minimal impact on VCA.

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