Encapsulated Cell Therapies in Sheep as a Translational Model - Trisha M. Fabijanic, B.S., University of Arizona, Tucson, AZ, Amy C. Kelly, Ph.D, University of Arizona, Tucson, AZ, Eliza H. Johnson, University of Arizona, Tucson, AZ, Delaney A. Drew, B.S., University of Arizona, Tucson, AZ, Demetri A. Vlachos, B.S., University of Arizona, Tucson, AZ, Charles W. Putnam, M.D., Ph.D., University of Arizona, Tucson, AZ, Sean W. Limesand, Ph.D., University of Arizona, Tucson, AZ, Klearchos K. Papas, Ph.D., University of Arizona, Tucson, AZ
Introduction:
Cell therapy has become increasingly studied for therapeutic use in drug delivery and regenerative medicine. Devices intended for implantation of cells require construction of membranes that can safely contain transplanted cells, provide a barrier to the host immune system and an outer vascularizing membrane to induce close vessel formation. Sheep make an excellent model because of their nearly comparable size, physiology, and disease profile with humans, as well as their docility, capacity for repeated blood draws, and ability to tolerate numerous implants during a single operation. In this study, sheep were implanted with devices containing allogeneic primary fetal sheep or xenogeneic Rat-2 fibroblasts to determine cell survival and immune response.
Methods:
Primary fetal sheep fibroblasts were isolated and cultured in RPMI. Rat-2 fibroblasts (ATCC) were cultured in DMEM. Cells were loaded into devices at different densities and transplanted subcutaneously. Sheep underwent allogeneic or xenogeneic transplantation with empty control and perforated devices transplanted as well. Devices were explanted at days 3, 7, 21 and 38 to evaluate host responses, vascularization, and cell survival through histological evaluation.
Results:
Sheep fibroblasts survived at different densities, confirming alloprotection with good vascularization and absence of a major foreign body response or extensive inflammation around the implants. Devices overloaded at the highest densities exhibited some host immune responses. Perforated devices exhibited a greater immune response that infiltrated the device. A robust immune response was seen around xenogeneic transplants with no encapsulated cells surviving.
Conclusion:
Sheep make a valuable translational animal model in cell therapy research. The results of this study concluded alloprotection in immunoisolating devices, allorejection in purposely perforated devices, and host immune response to xenogeneic transplantation, representing a feasible model for translational development of cell therapies. Future work will include continued allogeneic studies while avoiding xenogeneic rejection by incorporating immunomodulatory technologies.
