The TheraCyte™ Device Protects against Islet Allograft Rejection in Immunized Hosts

Abstract

Clinically, many candidates for islet transplantation are already immunized, which increases their risk of graft rejection. Encapsulation of pancreatic islets using the TheraCyte™ device has been shown to protect against allograft rejection in nonimmunized recipients. However, the capacity of the TheraCyte™ device to prevent rejection in immunized recipients has not yet been studied. In this study, the protective capacity of the TheraCyte™ device was evaluated in an allogeneic rat model. Lewis rats were used as islet donors, and nonimmunized (control) and alloimmunized, diabetic Wistar-Furth (WF) rats were used as recipients. Graft survival was shorter in immunized recipients than in nonimmunized recipients (mean survival, 5.3 ± 2.7 and 9.3 ± 1.6 days, respectively, p < 0.01) when nonencapsulated islets were transplanted under the kidney capsule. When islets were transplanted into the TheraCyte™ device, graft function was maintained during the 6-month study period in both immunized and nonimmunized rats. In oral glucose tolerance tests performed at 1 month after transplantation, both groups had similar insulin and blood glucose levels indicating similar metabolic functions. Volume densities and absolute volumes of tissue inside the devices 6 months after transplantation were also comparable between the two groups, indicating that both groups maintained similar amounts of endocrine tissue. A higher number of IFN-g-producing CD8+ T-cells were detected in immunized WF rats compared to control WF rats transplanted with encapsulated islets. This suggests that donor-specific alloreactivity in recipient rats was sustained throughout the study period. This study suggests that the TheraCyte™ device protects islet allografts also in immunized recipients. Our results further highlight the potential for using macroencapsulation to avoid immunosuppressive therapy in clinical islet transplantation.

Survival of encapsulated islets: More than a membrane story

“…The most inner leaf of this structure is supposed to create an immune barrier between the graft and the host immune system although the nominal pore size seems to be inadequate for this purpose. Rat islets implanted within this device were functional for 4 wk in immunocompromized mouse recipients [103] , for > 6 mo in allogeneic rat recipients [104] and for 30 d in a mouse model resembling autoimmune diabetes [105] . Also, reversal of diabetes for a 16wk period was reported when neonatal porcine islets were transplanted subcutaneously in nonobese diabetic mice [106] .…”

Long-term function and optimization of mouse and human islet transplantation in the subcutaneous device-less site

“…8,12,[14][15][16] It has been suggested that the lack of graft viability post-subcutaneous transplantation is due to the tissue's relatively low superficial tissue oxygen tension compared to other vascularized organs. 16 To thwart endogenous hypoxia and improve islet engraftment, subcutaneous engraftment strategies have employed growth factors, 17 scaffolds, 18-20 encapsulation polymers, 15,21 immunoisolating and non-immunoisolating devices, 11,[22][23][24][25][26] and oxygen delivery technologies. 17,24 While attractive due to the potential of avoiding systemic immunosuppression, a drawback of immunoisolating devices is the physical separation between host nutrient supply and the therapeutic cells within the device.…”

Immunoisolation to prevent tissue graft rejection: Current knowledge and future use

“…Itkin-Ansari's group showed that TheraCyte Õ was able to provide immune protection of pancreatic allograft in Rhesus monkeys for 1 year compared to a free graft, which did not last beyond 14 days. 55 A study by Kumagai-Braesch et al 56 showed that TheraCyte Õ supports islet allografts for six months in rats with normal and sensitized immune system. Bruin et al 57 showed that human embryonic stem cells can differentiate into pancreatic progenitors in TheraCyte Õ and were able to restore glucose levels in diabetic mice.…”