Cell transplantation and immunoisolation : studies on a macroencapsulation device

Abstract

Encapsulation of cellular grafts in semipermeable membranes may provide a way to protect the graft from immune attack without the need for pharmacological immunosuppression. In this thesis, the use of immunoisolating devices consisting of a bilaminar PTFE membrane was evaluated. Previous experimental studies indicate that these devices can protect cellular allografts from rejection. This thesis aims at improving our understanding of physiological factors influencing graft survival.

In the first study, the use of macroencapsulation for protection of human parathyroid allograft was evaluated. The following studies focused on the physiological milieu in the device by longitudinal investigations of the exchange of insulin and glucose across the membrane and the blood perfusion in the surrounding tissues. Finally, we evaluated whether implantation of the device 3 months before loading with islets improves graft survival.

The results can be summarized as follows. Allogeneic parathyroid tissue encapsulated in TheraCyte devices can survive for one year after transplantation in nonimmunosuppressed humans. However, marked growth of fibrotic tissue occurred in the devices. The exchange between the device lumen and microcirculation was reduced 1-4 weeks after implantation, but improved at 3 months and then no significant diffusion barrier seemed to be present. Histologically, the number of vascular profiles within 15 gm of the device surface was significantly increased as early as 2 weeks after implantation, while the number within 250 [my]m increased up to 3 months after implantation. Only the number of vessels within 250 [my]m showed a significant correlation to glucose kinetics. The blood perfusion in the s.c. tissue surrounding the device was lower at 4 weeks than on day I after implantation. It recovered at 2 months and then remained at a similar level for at least one year. The last study showed that if devices were preimplanted and loaded with islets in situ 3 months later, the survival of encapsulated syngeneic rat islets improved and the growth of fibrotic tissue in the device was reduced.

We conclude that microdialysis and laser Doppler are useful methods for evaluating the performance of a macroencapsulation device in vivo. Preimplantation of the TheraCyte device seems to be a promising way to improve the survival of the encapsulated graft.