Correlation of Chimerism with Acute Graft-versus-Host Disease in Rats following Liver Transplantation

Chen, Wei; Bai, Xueli; Xu, Guodong; Liang, Liang; Liang, Tingbo

doi:10.4061/2011/947150

Cited by 2 publications

(2 citation statements)

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“…The male specific gene sex-determining region Y (SRY) was used to measure the presence of male DNA and the 5HTT gene was used for total DNA content, as had been previously described for the detection of male/female chimerism within the rat (Xue, Chen et al, 2011). The level of chimerism ranged from approximately 55% up to 85% in recipients.…”

Section: Resultsmentioning

confidence: 99%

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Stem Cell Therapies and Radiological Imaging in Ataxia Telangiectasia

Dingwall¹

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ABSTRACT:Ataxia telangiectasia (A-T) is an autosomal recessive disorder associated with early childhood ataxia, neurodegeneration, immune deficiency, radiosensitivity, sterility, and an increased susceptibility to cancer. In spite of numerous years of research, there is still no curative treatment for A-T, nor a reliable animal model that recapitulates the prominent neurological phenotypes observed in patients. To address these deficiencies and investigate potential therapeutic approaches I have attempted to generate a universal donor pluripotent stem cell line, utilized radiological imaging to investigate a novel rat model of A-T, and tested whether bone marrow transplantation (BMT) could provide benefit in the treatment of hematological defects associated with A-T. Animal models are likely to play a key role in the development of therapeutic strategies for the treatment of A-T. While multiple mouse models of A-T currently exist and recapitulate some of the phenotypes attributed to the human disease, prominent neurodegeneration has not been observed in these animal. As such, our research group has produced a gene knock-out model in the rat, utilizing Zinc Finger Nuclease technology. Approximately 50% of the Atm -/-rats show dilated blood vessels in the eyes, microgliosis, and develop hind limb paralysis, suggesting this model may recapitulate some of the neurological defect observed in A-T patients. Magnetic resonance imaging (MRI) was utilized to assess structural changes in the brain and spinal cord. Surprisingly, no significant differences in cerebellar volume or gray/white matter ratios were observed in the brain or spinal cord of healthy animals.However, lymphomas were detected in the T12-L3 region of the spine in all of the paralysed animals tested. I utilized PET/MRI in conjunction with the radiotracer ( 18 F)PBR111, which is highly selective for the TSPO receptor of activated microglia in the brain, to assess microglial activation in vivo in 5 month old control and ATM null nonparalysed rats, three of each. No differences were observed in the cerebellum of these rats relative to WT rats, as well as multiple other brain regions assessed in healthy animals. These data provide evidence that paralysis in the A-T rat model is associated with the presence of lymphomas within the spinal column.

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Section: Resultsmentioning

confidence: 99%

“…Level of chimerism in the peripheral blood population was determined using real-time PCR as per (Xue, Chen et al, 2011). Blood samples were collected in a heparinised tube.…”

Section: Detection Of Engraftmentmentioning

confidence: 99%

Stem Cell Therapies and Radiological Imaging in Ataxia Telangiectasia

Dingwall¹

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

et al. 2019

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For patients with non-cirrhotic liver-based metabolic disorders, hepatocyte transplantation can be an effective treatment. However, long-term function of transplanted hepatocytes following infusion has not been achieved due to insufficient numbers of hepatocytes reaching the liver cell plates caused by activation of the instant blood-mediated inflammatory reaction (IBMIR). Our aim was to determine if the natural immune modulator, alpha-1 antitrypsin (AAT), could improve engraftment of transplanted hepatocytes and investigate its mechanism of action. A tubing loop model was used to analyse activation of the IBMIR when human hepatocytes were in contact with ABO-matched blood and 4 mg/ml AAT. Platelet and white cell counts, complement and cytokine expression were analysed. To determine if AAT could improve short-term engraftment, female rats underwent tail vein injection of AAT (120 mg/kg) or water (control) prior to the intrasplenic transplantation of 2 × 10 7 male hepatocytes. At 48 h and 1 week, livers were collected for analysis. In our loop model, human hepatocytes elicited a significant drop in platelet count with thrombus formation compared to controls. Loops containing AAT and hepatocytes showed no platelet consumption and no thrombus formation. Further, AAT treatment resulted in reduced IL-1β, IL-6 and IFN-γ and increased IL-1RA compared to untreated loops. In vivo, AAT significantly improved engraftment of rat hepatocytes compared to untreated at 48 h. AAT infusion may inhibit the IBMIR, thus improving short-term engraftment of donor hepatocytes and potentially improve the outcomes for patients with liver-based metabolic disease. Key messages • Alpha-1 antitrypsin (AAT) acts as an immune modulator to improve the efficacy of hepatocyte transplantation. • Treatment with AAT decreased thrombus formation and pro-inflammatory cytokine expression in a tubing loop model. • AAT significantly improved engraftment of donor hepatocytes within the first 48 h post transplantation. Electronic supplementary material The online version of this article (10.1007/s00109-019-01747-3) contains supplementary material, which is available to authorized users.

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Correlation of Chimerism with Acute Graft-versus-Host Disease in Rats following Liver Transplantation

Cited by 2 publications

References 32 publications

Stem Cell Therapies and Radiological Imaging in Ataxia Telangiectasia

Stem Cell Therapies and Radiological Imaging in Ataxia Telangiectasia

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

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