Pancreatic islets engineered with a FasL protein induce systemic tolerance at the induction phase that evolves into long-term graft-localized immune privilege
Open accessAbstract
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.
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FasL induced local immune tolerance by causing apoptosis in alloreactive T-cells and promoting the development of regulatory T-cells (Tregs) for long-term maintenance.
“They demonstrated that FasL induced local immune tolerance by causing apoptosis in alloreactive T-cells and as well as promoting the development of regulatory T-cells (Tregs) for long-term maintenance.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [115]
The Results report that SA-FasL-engineered islets induced death of alloreactive T cells, and the Discussion says Treg cells are required to maintain long-term graft-localized immune privilege. However, the Discussion presents generation of Tregs in the graft milieu as a possibility, not a demonstrated effect of FasL; it also distinguishes systemic tolerance during induction from local immune privilege during maintenance. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAllografts of isolated mouse islets engineered to transiently display FasL on their surface survived indefinitely if also treated for the first 15 days with rapamycin, whereas those without FasL were rejected within 30 days.
“Allografts were able to survive indefinitely if also treated for the first 15 days with rapamycin, whereas those without FasL were rejected within 30 days.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [115]
Local rather than systemic immune tolerance was highlighted by the transplantation of a second set of unmodified, donor matched cells that survived when grafted to the original transplantation site but were rejected when transplanted to the other kidney of the same mouse.
“The development of local rather than systemic immune tolerance was further highlighted by the transplantation of a second set of unmodified, donor matched cells that survived when grafted to the original transplantation site but were rejected when transplanted to the other kidney of the same mouse.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [115]
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Self-citationAdvancements and Challenges in Immune Protection Strategies for Islet Transplantation
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“Similar to our data, tolerance was antigen-and tissue-specific, as SA-FasL-engineered islets failed to protect third-party islet, donor-matched, and third-party skin recipients [23].”
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Sousa, A. R., Mano, J. F., & Oliveira, M. B. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.03.005 · Cited by 10 · see citing works
Biomaterial-based approaches to engineering immune tolerance
Emerson, A. E., Slaby, E. M., Hiremath, S. C., & Weaver, J. D. (2020) · Biomaterials Science · doi:10.1039/d0bm01171a · Cited by 12 · see citing works
Immune modulation for β-cell replacement in type 1 diabetes
Yang, Q., Song, Y.-H., Markmann, J., & Lei, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1785523 · Cited by 5 · see citing works
Engineering hypoimmune stem cell-derived beta cells
Licht, B. J. M., Duffy, G. P., & Levey, R. E. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04745-0 · Cited by 7 · see citing works
“This response was dependent on FoxP3 + Tregs, a finding which is further supported by similar studies in which SA-FasL-presenting microgels improved islet graft survival [39, 78, 80, 81].”
InfluentialAdenovirus-Mediated FasL Minigene Transfer Endows Transduced Cells with Killer Potential
Dumitrescu, M., Trusca, V., Savu, L., Stancu, I. G., Rațiu, A. C., Simionescu, M., & Gafencu, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176011 · Cited by 5
“Although under some pathological conditions the liver may be susceptible to apoptosis triggered by the Fas/FasL interaction [26], numerous studies have shown that therapeutic use of FasL in vivo does not cause liver toxicity [29,30].”
BackgroundNavigating challenges in human pluripotent stem cell-derived islet therapy for type 1 diabetes
Usama, M., Deng, Y., Chen, Y., Milland, T., Malleshaiah, M. K., & Aghazadeh, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1625439 · Cited by 3 · see citing works
“These fi ndings show streptavidin-anchored FasL (SA-FasL) induced apoptosis in Fas-expressing immune cells, with tolerance maintenance dependent on CD4 + CD25 + Foxp3 + Tregs and phagocyte-derived TGF-b in fully immunocompetent C57BL/6 mice (130).”
Shrestha, P., Turan, A., Batra, L., Gulen, A. E., Sun, Z., Tan, H., Askenasy, N., Shirwan, H., & Yolcu, E. (2023) · Blood Advances · doi:10.1182/bloodadvances.2022008495 · Cited by 3 · see citing works
“This notion is consistent with our recent studies demonstrating that SA-FasL–mediated tolerance to allogeneic islets involves apoptosis of Teff cells that culminates in a cascade of regulatory mechanisms involving phagocyte uptake of apoptotic bodies, secretion of TGF-β, and increased frequency of Treg cells that are…”
ResultSelf-citationKazmi, S., Tarique, M., Badal, D., Ulker, V., Turan, A., Yee-Flores, K. M., Nejma, A. J., Yolcu, E., & Shirwan, H. (2026) · JCI Insight · doi:10.1172/jci.insight.200686 · Cited by 1 · see citing works
“Engineering with both proteins did not compromise islet viability or metabolic functions, consistent with our previous studies using various immunomodulatory ligands (7, 13, 18, 25–27, 29, 38).”
Self-citationYee-Flores, K. M., Badal, D., Wright, N., Tarique, M., Yolcu, E., Wang, Y., & Shirwan, H. (2026) · Biomaterials Advances · doi:10.1016/j.bioadv.2026.215100
Self-citationWhat Is the Current State of Stem Cell Therapy in Diabetes?
Bakinowska, E., Biniek, W. J., Kiełbowski, K., Dyrka, K., Szewczyk, K., Ostałowska, H., Leciej, Z., & Pawlik, A. (2026) · Cells · doi:10.3390/cells15100907
“Presentation of the Fas ligand (FasL) on the surface of transplanted islets or biomaterials induces apoptosis of infiltrating Fas-expressing T lymphocytes, thereby limiting effector immune responses and promoting the establishment of localized immune privilege [56].”
Kuppan, P., Wong, J., Kelly, S., Lin, J.-X., Worton, J., Castro, C., Paramor, J., Seeberger, K., Anderson, C., Korbutt, G., et al. (2023) · bioRxiv · doi:10.1101/2023.02.14.528345
“It’s been reported that Treg cells traffic to allogeneic pancreatic islets immediately post transplantation in response to inflammatory cues, where they manifest their immunoregulatory function within the graft microenvironment (20).”
BackgroundResultInfluentialApplication and Progress of Stem Cells in the Treatment of Diabetes
朱, 家. (2021) · Bioprocess · doi:10.12677/bp.2021.114013
“期服用免疫抑制剂。如要解决这些问题,应寻找合适的种子细胞来代替人体胰岛,以供移植[17] [18] [19]。 干细胞诱导分化成 β 细胞,在一定程度上可解决供体不足和免疫排斥等问题,用以治疗糖尿病。自 从人类多能干细胞有望用于再生医学以来,已经对体外干细胞分化成胰岛素生成细胞(IPCs)有了深入研 究。体外产生胰岛细胞的来源主要包括胚胎干细胞(ESCs)和诱导多能干细胞(iPSCs))和成体干细胞。当前 生成 IPCs 的策略主要基于模拟正常胰腺发育的方法,在过去的十年多中,已经成功设计了许多诱导方法 在体外生成 IPCs [20] [21] [22] [23]。 Open Access”
- Authors
- Woodward, K. B., Zhao, H., Shrestha, P., Batra, L., Tan, M., Grimany-Nuno, O., Bandura-Morgan, L., Askenasy, N., Shirwan, H., & Yolcu, E. S.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Shirwan, Haval
- Yolcu, Esma S.
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 20
- Issue
- 5
- Pages
- 1285-1295
- ISSN
- 1600-6135 (ISSN-L)
- PMC
- PMC7299172
- OpenAlex
- W2995235591
- Cited by
- 35
- References
- 63
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 7 · 2018: 1
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association (1‐12‐BS‐191)
- National Institutes of Health (R56AI121281, R21AI113348‐01, R01AI121281, U01AI132817, 5T32 HL076138)
- W. M. Keck Foundation
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- pancreatic islets, Fas ligand, islet transplantation, allograft tolerance, regulatory T cells, TGF-beta, alloreactive T cells, streptozotocin, donor antigens, type 1 diabetes
- MeSH terms
- Immune Privilege, Graft Survival, Immune Tolerance, Islets of Langerhans, Islets of Langerhans Transplantation, Fas Ligand Protein
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