The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets

Abstract

■ AbstractDespite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. This warrants the need for a suitable small animal model. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. In this model, human T cell engraftment could be achieved, and CD45 + cells were observed in the spleen and peripheral blood. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10.

Characterisation of the Xenogeneic Immune Response to Microencapsulated Fetal Pig Islet-Like Cell Clusters Transplanted into Immunocompetent C57BL/6 Mice

“…This is consistent with previous findings which showed a negative correlation between the PFO and cell viability with anti-porcine antibodies being detected in mouse sera within 5 to 14 days post-transplantation [14], [17]. The possibility that an immune response is not elicited against the alginate material itself can be ruled out as empty barium alginate microcapsules retrieved at 21 days post-transplantation were free of PFO consistent with our earlier studies [21], [26]. These findings suggest that xenoantigens and cytokines permeating through the porous alginate microcapsules lead to inflammation and the PFO.…”

“…Retrieved capsules (n = 100) from each recipient mouse were examined under a light microscope for the degree of cellular/fibrotic overgrowth using a scoring system as described previously [21] where score 0  =  no overgrowth, score 1 = <25% of overgrowth, score 2 = 25–50%, score 3 = 51–75% and score 4 = >75% of overgrowth.…”

Islet Transplantation and Encapsulation: An Update on Recent Developments

“…This study emphasizes the fact that thorough validation of different animal models is essential to predict the clinical outcome with encapsulated islets. Our recent study reveals that even a humanized NOD mouse model does not mirror the fibrotic response observable in humans adequately, as fibrotic overgrowth is almost absent after several weeks of transplantation [123]. The small fibrotic overgrowth around the microencapsulated human islets failed to stop the encapsulated islets from functioning in the diabetic recipient mice.…”

Encapsulation technologies in beta cell replacement therapies for Type 1 diabetes

“…Incorporation of biological factors like fibroblast growth factor 1 (FGF-1) [141], vascular endothelial growth factor (VEGF) [142], anti-coagulants [143], anti-inflammatory molecules [144][145][146][147][148], immunoregulatory biomolecules like CXCL12 [149] and co-encapsulation with tolerogenic mesenchymal stem cells [150] are all currently being investigated to improve bioencapsulation device outcomes.…”