Pancreatic Islets Engineered to Display on Their Surface an Exogenous FasL Protein Survive Indefinitely in Allogeneic Recipients

Objective: To engineer pancreatic islets in a rapid and efficient manner with a novel form of FasL protein and test the efficacy of engineered islets for long‐term survival in allogeneic hosts. Methods: BALB/c islets were engineered by cell surface modification with biotin followed by the display of a chimeric form of FasL protein with core streptavidin (SA‐FasL). SA‐FasL‐engineered islets were transplanted into streptozotocin diabetic C57BL/6 mice under transient cover of rapamycin. Results: All the islets showed effective engineering with SA‐FasL, which persisted on the surface of islets for weeks in vitro as assessed by confocal microscopy. All the islets (n=23) with SA‐FasL survived over 100–360 days without detectable signs of rejection. In marked contrast, all the unmodified (n=9) and SA‐engineered (n=14) islets underwent acute rejection within 40 days. The observed tolerance was localized to the engineered islets as unmodified second set of islets transplanted under contralateral kidney of long‐term (>90 days) graft recipients were rejected in a normal tempo (MST=17 ± 9 days) without any effect on the survival of primary islets. Conclusion: Engineering pancreatic islets with exogenous immunomodulatory molecules, such as SA‐FasL, in a rapid and efficient manner represents a novel means of immunomodulation with considerable therapeutic potential. NIH (R21 DK61333, R01 AI47864, R21 AI057903 , R21 HL080108 ), JDRF (1‐2001‐328), and ADA (1‐05‐JF‐56).