Pancreatic islets engineered with a FasL protein induce systemic tolerance at the induction phase that evolves into long-term graft-localized immune privilege

Autor: Kyle B. Woodward, Pradeep Shrestha, Esma S. Yolcu, Hong Zhao, Haval Shirwan, Orlando Grimany-Nuno, Laura Bandura-Morgan, Lalit Batra, Nadir Askenasy, Min Tan
Rok vydání: 2020
Předmět:
Zdroj: Am J Transplant
ISSN: 1600-6135
DOI: 10.1111/ajt.15747
Popis: We have previously shown that pancreatic islets engineered to transiently display a modified form of FasL protein (SA-FasL) on their surface survive indefinitely in allogeneic recipients without a need for chronic immunosuppression. Mechanisms that confer long-term protection to allograft are yet to be elucidated. We herein demonstrated that immune protection evolves in two distinct phases; induction and maintenance. SA-FasL-engineered allogeneic islets survived indefinitely and conferred protection to a second set of donor-matched, but not third party, unmanipulated islet grafts simultaneously transplanted under the contralateral kidney capsule. Protection at the induction phase involved a reduction in the frequency of proliferating alloreactive T cells in the graft-draining lymph nodes, and required phagocytes and TGF-β. At the maintenance phase, immune protection evolved into graft site-restricted immune privilege as the destruction of long-surviving SA-FasL-islet grafts by streptozotocin followed by the transplantation of a second set of unmanipulated islet grafts into the same site from the donor, but not third party, resulted in indefinite survival. The induced immune privilege required both CD4(+)CD25(+)Foxp3(+) Treg cells and persistent presence of donor antigens. Engineering cell and tissue surfaces with SA-FasL protein provides a practical, efficient, and safe means of localized immunomodulation with important implications for autoimmunity and transplantation.
Databáze: OpenAIRE
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