First Author | Batra L | Year | 2020 |
Journal | J Immunol | Volume | 204 |
Issue | 10 | Pages | 2840-2851 |
PubMed ID | 32253240 | Mgi Jnum | J:291169 |
Mgi Id | MGI:6431983 | Doi | 10.4049/jimmunol.2000055 |
Citation | Batra L, et al. (2020) Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression. J Immunol 204(10):2840-2851 |
abstractText | Allogeneic islet transplantation is limited by adverse effects of chronic immunosuppression used to control rejection. The programmed cell death 1 pathway as an important immune checkpoint has the potential to obviate the need for chronic immunosuppression. We generated an oligomeric form of programmed cell death 1 ligand chimeric with core streptavidin (SA-PDL1) that inhibited the T effector cell response to alloantigens and converted T conventional cells into CD4(+)Foxp3(+) T regulatory cells. The SA-PDL1 protein was effectively displayed on the surface of biotinylated mouse islets without a negative impact islet viability and insulin secretion. Transplantation of SA-PDL1-engineered islet grafts with a short course of rapamycin regimen resulted in sustained graft survival and function in >90% of allogeneic recipients over a 100-d observation period. Long-term survival was associated with increased levels of intragraft transcripts for innate and adaptive immune regulatory factors, including IDO-1, arginase-1, Foxp3, TGF-beta, IL-10, and decreased levels of proinflammatory T-bet, IL-1beta, TNF-alpha, and IFN-gamma as assessed on day 3 posttransplantation. T cells of long-term graft recipients generated a proliferative response to donor Ags at a similar magnitude to T cells of naive animals, suggestive of the localized nature of tolerance. Immunohistochemical analyses showed intense peri-islet infiltration of T regulatory cells in long-term grafts and systemic depletion of this cell population resulted in prompt rejection. The transient display of SA-PDL1 protein on the surface of islets serves as a practical means of localized immunomodulation that accomplishes sustained graft survival in the absence of chronic immunosuppression with potential clinical implications. |