Session Time: 3:15pm-4:45pm
Presentation Time: 3:27pm-3:39pm
*Purpose: Allogenic islet transplantation is an effective therapeutic approach for the treatment of T1D. However, chronic immunosuppression to control rejection is a major limitation. The PD-1 pathway is exploited by cancer for immune evasion and its blockade has been shown to result in impressive clinical outcomes for various cancers. We herein assessed whether localized modulation of PD-1 pathway has efficacy in preventing islet graft rejection.
*Methods: A synthetic gene consisting of the functional domain of mouse PD-L1 N-terminus to core streptavidin (SA-PDL1) was designed and expressed in insect cells. The SA-PDL1 protein was transiently displayed on the surface of cells and islets that had been biotinylated taking the advantage of high affinity interaction between biotin and SA. BALB/c islets were engineered with SA-PDL1 and transplanted under the kidney capsule of diabetic C57BL/6 mice to assess graft survival and function.
*Results: SA-PDL1 protein was successfully expressed and purified. The protein exists as oligomers with immunoregulatory function for conversion of Teffs into Tregs and blocking alloantigen-driven Teff proliferation. SA-PDL1 showed dose-dependent attachment to the surface of biotinylated splenocytes and islets. The surface display of SA-PDL1 did not impact islet survival or insulin secretion. Importantly, > 90% of SA-PDL1-engineered islet grafts (n=12) transplanted under a 15-day rapamycin regimen survived > 100-day observation period. In contrast, controls with rapamycin regimen only showed acute rejection (n=9; MST=19 days). Immunohistochemistry of long-term grafts showed the presence of CD4+FoxP3+ Treg cells in patches at the periphery of the graft. Splenocytes from long-term graft recipients generated T cell proliferative responses to donor alloantigens at levels comparable to those of rejecting or naïve controls, demonstrating graft-localized nature of immune unresponsiveness.
*Conclusions: The display of SA-PDL1 protein on islet surface provides an effective and practical alternative to systemic chronic immunosuppression to overcome rejection with significant clinical potential.
To cite this abstract in AMA style:Batra L, Shrestha P, Zhao H, Woodward KB, Tan M, Nuno OG, Togay A, Coronel MM, Garcia AJ, Shirwan H, Yolcu ES. Immune Checkpoint PD-L1 Pathway as an Effective Platform for Localized Immunomodulation to Attain Indefinite Allogeneic Islet Graft Survival [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/immune-checkpoint-pd-l1-pathway-as-an-effective-platform-for-localized-immunomodulation-to-attain-indefinite-allogeneic-islet-graft-survival/. Accessed September 20, 2021.
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