CoChat
Sign Up
Cited by 82Pancreatic function and diabetesT-cell and B-cell ImmunologyDiabetes and associated disorders

Pancreatic Islets Engineered with SA-FasL Protein Establish Robust Localized Tolerance by Inducing Regulatory T Cells in Mice

Open access
Yolcu, Esma S, Zhao, Hong, Bandura-Morgan, Laura, Lacelle, Chantale, Woodward, Kyle B, Askenasy, Nadir, Shirwan, Haval·2011·The Journal of Immunology
DOI 10.4049/jimmunol.1003266PMC PMC3232043
Open this paper in CoChat — free accountOpen PDF

Abstract

Allogeneic islet transplantation is an important therapeutic approach for the treatment of type 1 diabetes. Clinical application of this approach, however, is severely curtailed by allograft rejection primarily initiated by pathogenic effector T cells regardless of chronic use of immunosuppression. Given the role of Fas-mediated signaling in regulating effector T cell responses, we tested if pancreatic islets can be engineered ex vivo to display on their surface an apoptotic form of Fas ligand protein chimeric with streptavidin (SA-FasL) and whether such engineered islets induce tolerance in allogeneic hosts. Islets were modified with biotin following efficient engineering with SA-FasL protein that persisted on the surface of islets for >1 wk in vitro. SA-FasL–engineered islet grafts established euglycemia in chemically diabetic syngeneic mice indefinitely, demonstrating functionality and lack of acute toxicity. Most importantly, the transplantation of SA-FasL–engineered BALB/c islet grafts in conjunction with a short course of rapamycin treatment resulted in robust localized tolerance in 100% of C57BL/6 recipients. Tolerance was initiated and maintained by CD4+CD25+Foxp3+ regulatory T (Treg) cells, as their depletion early during tolerance induction or late after established tolerance resulted in prompt graft rejection. Furthermore, Treg cells sorted from graft-draining lymph nodes, but not spleen, of long-term graft recipients prevented the rejection of unmodified allogeneic islets in an adoptive transfer model, further confirming the Treg role in established tolerance. Engineering islets ex vivo in a rapid and efficient manner to display on their surface immunomodulatory proteins represents a novel, safe, and clinically applicable approach with important implications for the treatment of type 1 diabetes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.4049/jimmunol.1003266

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [114]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Allografts 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 [114]

  • 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 [114]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 49 · Cited by 82

Research works printed but not linked: 47

  1. [1]Nakayama M Beilke JN Jasinski JM Kobayashi M Miao D Li M Coulombe MG Liu E Elliott JF Gill RG Eisenbarth GS Priming and effector dependence on insulin B:9–23 peptide in NOD islet autoimmunity J. Clin. Invest 2007 117 1835 1843 17607359 PMC1904318
  2. [3]Yoon JW Yoon CS Lim HW Huang QQ Kang Y Pyun KH Hirasawa K Sherwin RS Jun HS Control of autoimmune diabetes in NOD mice by GAD expression or suppression in beta cells Science 1999 284 1183 1187 10325232
  3. [4]Shapiro AM Ricordi C Hering BJ Auchincloss H Lindblad R Robertson RP Secchi A Brendel MD Berney T Brennan DC Cagliero E Alejandro R Ryan EA DiMercurio B Morel P Polonsky KS Reems JA Bretzel RG Bertuzzi F Froud T Kandaswamy R Sutherland DE Eisenbarth G Segal M Preiksaitis J Korbutt GS Barton FB Viviano L Seyfert-Margolis V Bluestone J Lakey JR International trial of the Edmonton protocol for islet transplantation N. Engl. J. Med 2006 355 1318 1330 17005949
  4. [5]Alejandro R Lehmann R Ricordi C Kenyon NS Angelico MC Burke G Esquenazi V Nery J Betancourt AE Kong SS Miller J Mintz DH Long-term function (6 years) of islet allografts in type 1 diabetes Diabetes 1997 46 1983 1989 9392484
  5. [6]Haskins K McDuffle M Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone Science 1990 249 1433 1435 2205920
  6. [7]Yolcu ES Ash S Kaminitz A Sagiv Y Askenasy N Yarkoni S Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression Immunol. Cell Biol 2008 86 650 658 18794907
  7. [8]Ju S-T Panka DJ Cul H Ettinger R El-Khatib M Sherr DH Stanger BZ Marshak-Rothstein A Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation Nature 1996 373 444 448 7530337
  8. [9]O'Reilly LA Tai L Lee L Kruse EA Grabow S Fairlie WD Haynes NM Tarlinton DM Zhang JG Belz GT Smyth MJ Bouillet P Robb L Strasser A Membrane-bound Fas ligand only is essential for Fas-induced apoptosis Nature 2009 461 659 663 19794494 PMC2785124
  9. [10]Arai H Chan SY Bishop DK Nabel GJ Inhibition of the alloantibody response by CD95 ligand Nat. Med 1997 3 843 848 9256273
  10. [11]Kang SM Schneider DB Lin Z Hanahan D Dichek DA Stock PG Baekkeskov S Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction Nat. Med 1997 3 738 743 9212099
  11. [12]Lau HT Yu M Fontana A Stoeckert CJ Jr Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice Science 1996 273 109 112 8658177
  12. [13]Matsue H Matsue K Walters M Okumura K Yagita H Takashima A Induction of antigen-specific immunosuppression by CD95L cDNA-transfected 'killer' dendritic cells Nat. Med 1999 5 930 937 10426318
  13. [14]Min WP Gorczynski R Huang XY Kushida M Kim P Obataki M Lei J Suri RM Cattral MS Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival J. Immunol 2000 164 161 167 10605007
  14. [15]Tourneur L Malassagne B Batteux F Fabre M Mistou S Lallemand E Lores P Chiocchia G Transgenic expression of CD95 ligand on thyroid follicular cells confers immune privilege upon thyroid allografts J. Immunol 2001 167 1338 1346 11466351
  15. [16]Yolcu ES Askenasy N Singh NP Cherradi SE Shirwan H Cell membrane modification for rapid display of proteins as a novel means of immunomodulation: FasL-decorated cells prevent islet graft rejection Immunity 2002 17 795 808 12479825
  16. [17]Yolcu ES Gu X Lacelle C Zhao H Bandura-Morgan L Askenasy N Shirwan H Induction of tolerance to cardiac allografts using donor splenocytes engineered to display on their surface an exogenous fas ligand protein J. Immunol 2008 181 931 939 18606644 PMC2593473
  17. [18]Kilinc MO Mukundan L Yolcu ES Singh NP Suttles J Shirwan H Generation of a multimeric form of CD40L with potent immunostimulatory activity using streptavidin as a chaperon Exp. Mol. Pathol 2006 80 252 261 16487512
  18. [19]Elpek KG Lacelle C Singh NP Yolcu ES Shirwan H CD4+CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early, but not late phases of tumor development in a B cell lymphoma model J. Immunol 2007 178 6840 6848 17513732
  19. [20]Morice WG Brunn GJ Wiederrecht G Siekierka JJ Abraham RT Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes J. Biol. Chem 1993 268 3734 3738 8429048
  20. [21]Wells AD Li XC Li Y Walsh MC Zheng XX Wu Z Nunez G Tang A Sayegh M Hancock WW Strom TB Turka LA Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance Nat. Med 1999 5 1303 1307 10545998
  21. [22]Battaglia M Stabilini A Roncarolo MG Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells Blood 2005 105 4743 4748 15746082
  22. [23]Delgoffe GM Kole TP Zheng Y Zarek PE Matthews KL Xiao B Worley PF Kozma SC Powell JD The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment Immunity 2009 30 832 844 19538929 PMC2768135
  23. [24]Feuerer M Shen Y Littman DR Benoist C Mathis D How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets Immunity 2009 31 654 664 19818653 PMC2998796
  24. [25]Lennon GP Bettini M Burton AR Vincent E Arnold PY Santamaria P Vignali DA T cell islet accumulation in type 1 diabetes is a tightly regulated, cell-autonomous event Immunity 2009 31 643 653 19818656 PMC2763021
  25. [26]Setiady YY Coccia JA Park PU In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti-CD25 monoclonal antibody is mediated by FcgammaRIII+ phagocytes Eur. J. Immunol 2010 40 780 786 20039297
  26. [27]Chen JJ Sun Y Nabel GJ Regulation of the proinflammatory effects of Fas ligand (CD95L) Science 1998 282 1714 1717 9831564
  27. [28]Kang SM Braat D Schneider DB O'Rourke RW Lin Z Ascher NL Dichek DA Baekkeskov S Stock PG A non-cleavable mutant of Fas ligand does not prevent neutrophilic destruction of islet transplants Transplantation 2000 69 1813 1817 10830216
  28. [29]Ottonello L Tortolina G Amelotti M Dallegri F Soluble Fas ligand is chemotactic for human neutrophilic polymorphonuclear leukocytes J. Immunol 1999 162 3601 3606 10092820
  29. [30]Dhein J Walczak H Bäumler C Debatin K-M Krammer PH Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature 1995 373 438 441 7530335
  30. [31]Swenson KM Ke B Wang T Markowitz JS Maggard MA Spear GS Imagawa DK Goss JA Busuttil RW Seu P Fas ligand gene transfer to renal allografts in rats: effects on allograft survival Transplantation 1998 65 155 160 9458007
  31. [32]Takeuchi T Ueki T Nishimatsu H Kajiwara T Ishida T Jishage K Ueda O Suzuki H Li B Moriyama N Kitamura T Accelerated rejection of Fas ligand-expressing heart grafts J. Immunol 1999 162 518 522 9886428
  32. [33]Tanaka M Itai T Adachi M Nagata S Downregulation of Fas ligand by shedding Nat. Med 1998 4 31 36 9427603
  33. [34]Seino K Iwabuchi K Kayagaki N Miyata R Nagaoka I Matsuzawa A Fukao K Yagita H Okumura K Chemotactic activity of soluble Fas ligand against phagocytes J. Immunol 1998 161 4484 4488 9794371
  34. [35]Suda T Hashimoto H Tanaka M Ochi T Nagata S Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing J. Exp. Med 1997 186 2045 2050 9396774 PMC2199173
  35. [36]Siegel RM Frederiksen JK Zacharias DA Chan FK Johnson M Lynch D Tsien RY Lenardo MJ Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations Science 2000 288 2354 2357 10875918
  36. [37]Franke DDS Yolcu ES Alard P Kosiewicz MM Shirwan H A novel multimeric form of FasL modulates the ability of diabetogenic T cells to mediate type 1 diabetes in an adoptive transfer model Mol. Immunol 2007 44 2884 2892 17324464 PMC1950258
  37. [38]Kendal AR Chen Y Regateiro FS Ma J Adams E Cobbold SP Hori S Waldmann H Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance J. Exp. Med 2011 Epub ahead of print PMC3182049 21875958
  38. [39]Perruche S Zhang P Liu Y Saas P Bluestone JA Chen W CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells Nat. Med 2008 14 528 535 18438416
  39. [40]Baatar D Olkhanud P Sumitomo K Taub D Gress R Biragyn A Human peripheral blood T regulatory cells (Tregs), functionally primed CCR4+ Tregs and unprimed J. Immunol 2007 178 4891 4900 17404270 PMC2262930
  40. [41]Strauss L Bergmann C Whiteside TL Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis J. Immunol 2009 182 1469 1480 19155494 PMC3721355
  41. [42]Kilinc MO Rowswell-Turner RB Gu T Virtuoso LP Egilmez NK Activated CD8+ T-effector/memory cells eliminate CD4+ CD25+ Foxp3+ T-suppressor cells from tumors via FasL mediated apoptosis J. Immunol 2009 183 7656 7660 19923444
  42. [43]Chen A Liu S Park D Kang Y Zheng G Depleting intratumoral CD4+CD25+ regulatory T cells via FasL protein transfer enhances the therapeutic efficacy of adoptive T cell transfer Cancer Res 2007 67 1291 1298 17283166
  43. [44]Reardon C Wang A McKay DM Transient local depletion of Foxp3+ regulatory T cells during recovery from colitis via Fas/Fas ligand-induced death J. Immunol 2008 180 8316 8326 18523298
  44. [45]Banz A Pontoux C Papiernik M Modulation of Fas-dependent apoptosis: a dynamic process controlling both the persistence and death of CD4 regulatory T cells and effector T cells J. Immunol 2002 169 750 757 12097377
  45. [46]Kaminitz A Yolcu ES Stein J Yaniv I Shirwan H Askenasy N Killer Treg restore immune homeostasis and suppress autoimmune diabetes in prediabetic NOD mice J. Autoimmun 2011 37 39 47 21497486
  46. [47]Kaminitz A Yolcu ES Askenasy EM Stein J Yaniv I Shirwan H Askenasy N Effector and Naturally Occurring Regulatory T Cells Display No Abnormalities in Activation Induced Cell Death in NOD Mice PLoS. One 2011 6 e21630 21738739 PMC3124542
  47. [48]Strauss L Czystowska M Szajnik M Mandapathil M Whiteside TL Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin PLoS. One 2009 4 e5994 19543393 PMC2694984

Authors
Yolcu, E. S., Zhao, H., Bandura-Morgan, L., Lacelle, C., Woodward, K. B., Askenasy, N., & Shirwan, H.
Affiliations
  • University of Louisville (US)
  • Institute for Cellular Therapeutics, University of Louisville , Louisville, KY 40202
  • Schneider Children's Medical Center (IL)
Corresponding author
  • Zhao, Hong
  • Lacelle, Chantale
  • Shirwan, Haval
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2011-12-01
Volume
187
Issue
11
Pages
5901-5909
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.1003266
PMC
PMC3232043
OpenAlex
W1805798838
Cited by
82
References
49
Citations by year
2026: 4 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 9 · 2018: 7 · 2017: 6 · 2016: 3 · 2015: 6 · 2014: 5 · 2013: 4 · 2012: 2
FWCI
3.60
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of Louisville
  • National Heart, Lung, and Blood Institute (T32HL076138)
  • National Institute of Allergy and Infectious Diseases (R21AI057903)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R43DK079394, R41 DK077242)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
type 1 diabetes, allogeneic islet transplantation, Fas ligand, regulatory T cells, allograft rejection, effector T cells, rapamycin, adoptive transfer, immunomodulatory proteins
MeSH terms
Animals, Diabetes Mellitus, Type 1, Graft Rejection, Immune Tolerance, Immunohistochemistry, Indicators and Reagents, Islets of Langerhans, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Recombinant Fusion Proteins, Transplantation, Homologous, Islets of Langerhans Transplantation, Adoptive Transfer, Streptavidin, T-Lymphocytes, Regulatory, Mice, Fas Ligand Protein

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review