BACKGROUND: A major barrier to the clinical application of xenotransplantation as a treatment option for patients is T cell-mediated rejection. Studies based on experimental rodent models of xenograft tolerance or rejection in vivo have provided useful information about the role of T cell immune response in xenotransplantation. However not all observations seen in rodents faithfully recapitulate the human situation This study aimed to establish a humanized mouse model of xenotransplantation, which mimics xenograft rejection in the context of the human immune system. METHODS: NOD-SCID IL2rγ -/- mice were transplanted with neonatal porcine islet cell clusters (NICC) followed by reconstitution of human peripheral blood mononuclear cells (PBMC). Human leukocyte engraftment and islet xenograft rejection were confirmed by flow cytometric and histological analyses. RESULTS: In the absence of human PBMC, porcine NICC transplanted into NOD-SCID IL2rγ -/- mice revealed excellent graft integrity and endocrine function. Human PBMC demonstrated a high level of engraftment in NOD-SCID IL2rγ -/- mice. Reconstitution of NICC recipient NOD-SCID IL2rγ -/- mice with human PBMC led to the rapid destruction of NICC xenografts in a PBMC number-dependent manner. CONCLUSIONS: Human PBMC-reconstituted NOD-SCID IL2rγ -/- mice provide an ideal model to study human immune responses in xenotransplantation. Studies based on this humanized mouse model will provide insight for improving the outcomes of clinical xenotransplantation.
BACKGROUND:Pig islet xenotransplantation has the potential to overcome the shortage of donated human islets for islet cell transplantation in type 1 diabetes.Testing in nonhuman primate models is necessary before clinical application in humans.Intraportal islet transplantation in monkeys is usually performed by surgical infusion during laparotomy or laparoscopy.In this paper,we describe a new method of percutaneous transhepatic portal catheterization(PTPC) as an alternative to current methods of islet transplantation in rhesus monkeys.METHODS:We performed ultrasound-guided PTPC in five adult rhesus monkeys weighing 7-8 kg,with portal vein catheterization confirmed by digital subtraction angiography.We monitored for complications in the thoracic and abdominal cavity.To evaluate the safety of ultrasound-guided PTPC,we recorded the changes in portal pressure throughout the microbead transplantation procedure.RESULTS:Ultrasound-guided PTPC and infusion of 16 000 microbeads/kg body weight into the portal vein was successful in all five monkeys.Differences in the hepatobiliary anatomy of rhesus monkeys compared to humans led to a higher initial complication rate.The first monkey died of abdominal hemorrhage 10 hours post-transplantation.The second suffered from a mild pneumothorax but recovered fully after taking only conservative measures.After gaining experience with the first two monkeys,we decreased both the hepatic puncture time and the number of puncture attempts required,with the remaining three monkeys experiencing no complications.Portal pressures initially increased proportional to the number of transplanted microbeads but returned to preinfusion levels at 30 minutes post-transplantation.The changes in portal pressures occurring during the procedure were not significantly different.CONCLUSIONS:Ultrasound-guided PTPC is an effective,convenient,and minimally invasive method suitable for use in non-human primate models of islet cell transplantation provided that care is taken with hepatic puncture.Its advantages
Feng Gao,Shao-Dong Ai,Sheng Liu,Wen-Bin Zeng and Wei Wang Cell Transplantation & Gene Therapy Institute and Department of Ultrasound , Third Xiangya Hospital
