Localized immune tolerance from FasL-functionalized PLG scaffolds

Area of Science:

• Regenerative Medicine
• Immunology
• Biomaterials Science

Background:

• Intraportal islet transplantation for type 1 diabetes (T1D) faces limitations including liver placement and chronic immunosuppression.
• Developing strategies for extrahepatic islet engraftment without long-term immunosuppression is crucial for T1D therapy.

Purpose of the Study:

• To investigate the efficacy of localized immunomodulation with streptavidin-FasL (SA-FasL) on microporous scaffolds for allogeneic islet transplantation.
• To assess the potential of SA-FasL-functionalized scaffolds to support islet survival and function at an extrahepatic site without chronic immunosuppression.

Main Methods:

• Allogeneic islets were modified with biotin and transplanted onto SA-FasL-conjugated biotinylated poly(lactide-co-glycolide) (PLG) scaffolds into the peritoneal fat.
• A short course of rapamycin was administered.
• Scaffolds were engineered for efficient SA-FasL conjugation and assessed for their ability to induce apoptosis in Fas receptor-expressing cells.

Main Results:

• SA-FasL-functionalized scaffolds facilitated robust engraftment of allogeneic islets.
• Transplanted islets demonstrated sustained survival and restored normoglycemia for 200 days.
• Neither transplantation without rapamycin nor without SA-FasL supported long-term islet survival and function.

Conclusions:

• Microporous scaffolds functionalized with SA-FasL enable successful allogeneic islet engraftment and long-term function in an extrahepatic location.
• This strategy effectively eliminates the need for chronic immunosuppression in T1D treatment.
• SA-FasL-modified scaffolds represent a significant advancement with high potential for clinical translation.