Abstract
We have successfully established and characterized a genetically modified pig line with ubiquitous expression of LEA29Y, a human CTLA4-Ig derivate. LEA29Y binds human B7.1/CD80 and B7.2/CD86 with high affinity and is thus a potent inhibitor of T cell co-stimulation via this pathway. We have characterized the expression pattern and the biological function of the transgene as well as its impact on the porcine immune system and have evaluated the potential of these transgenic pigs to propagate via assisted breeding methods. The analysis of LEA29Y expression in serum and multiple organs of CAG-LEA transgenic pigs revealed that these animals produce a biologically active transgenic product at a considerable level. They present with an immune system affected by transgene expression, but can be maintained until sexual maturity and propagated by assisted reproduction techniques. Based on previous experience with pancreatic islets expressing LEA29Y, tissues from CAG-LEA29Y transgenic pigs should be protected against rejection by human T cells. Furthermore, their immune-compromised phenotype makes CAG-LEA29Y transgenic pigs an interesting large animal model for testing human cell therapies and will provide an important tool for further clarifying the LEA29Y mode of action.
Highlights
Xenotransplantation, the use of living cells, tissues or organs of animal origin for the treatment of human patients, is a promising approach for overcoming donor organ shortages
We found that the binding domain of CTLA4 is strongly conserved among the examined species, whereas the homology in B7.1/CD80 and B7.2/CD86 is lower (Fig 1)
This is supported by the identification of positively selected sites, where B7.2/CD86 and B7.1/CD80 showed a tendency toward evolutionary adaption in mammals, whereas this tendency was revealed only for two positions in CTLA4
Summary
Xenotransplantation, the use of living cells, tissues or organs of animal origin for the treatment of human patients, is a promising approach for overcoming donor organ shortages. The ubiquitous CTLA4-Ig or LEA29Y expression across a range of porcine tissues or organs potentially attractive for transplantation would be preferable. Such a ubiquitous abundance of T cell blocking agents might, result in a chronic impairment of the immune system in the donor organism, which would affect the reproducibility of these animals, and the availability of donor organs. A transgenic pig with an inducible expression of porcine CTLA4-Ig did not show an affected immune system, but the suitability of such organs in transplantation experiments remains elusive [9]. Pigs that constitutively produce porcine CTLA4-Ig [10] were severely immunocompromised and could not be maintained for propagation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
