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ResearchIn-Press PreviewImmunology Open Access | 10.1172/JCI178975

Maintenance of graft tissue-resident Foxp3+ cells is necessary for lung transplant tolerance in mice

Wenjun Li,1 Yuriko Terada,1 Yun Zhu Bai,1 Yuhei Yokoyama,1 Hailey M. Shepherd,1 Junedh M. Amrute,2 Amit I. Bery,2 Zhiyi Liu,1 Jason M. Gauthier,1 Marina Terekhova,3 Ankit Bharat,4 Jon H. Ritter,3 Varun Puri,1 Ramsey R. Hachem,2 Hēth R. Turnquist,5 Peter T. Sage,6 Alessandro Alessandrini,7 Maxim N. Artyomov,3 Kory J. Lavine,2 Ruben G. Nava,1 Alexander S. Krupnick,8 Andrew E. Gelman,1 and Daniel Kreisel1

1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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1Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

2Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

4Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, United States of America

5Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

6Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, United States of America

8Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, United States of America

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Published March 18, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI178975.
Copyright © 2025, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 18, 2025 - Version history
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Abstract

Mechanisms that mediate allograft tolerance differ between organs. We have previously shown that Foxp3+ T cell-enriched bronchus-associated lymphoid tissue (BALT) is induced in tolerant murine lung allografts and that these Foxp3+ cells suppress alloimmune responses locally and systemically. Here, we demonstrated that Foxp3+ cells that reside in tolerant lung allografts differed phenotypically and transcriptionally from those in the periphery and were clonally expanded. Using a mouse lung re-transplant model, we showed that recipient Foxp3+ cells were continuously recruited to the BALT within tolerant allografts. We identified distinguishing features of graft-resident and newly recruited Foxp3+ cells and showed that graft-infiltrating Foxp3+ cells acquired transcriptional profiles resembling those of graft-resident Foxp3+ cells over time. Allografts underwent combined antibody-mediated rejection (AMR) and acute cellular rejection (ACR) when recruitment of recipient Foxp3+ cells was prevented. Finally, we showed that local administration of IL-33 could expand and activate allograft-resident Foxp3+ cells providing a platform for the design of tolerogenic therapies for lung transplant recipients. Our findings establish graft-resident Foxp3+ cells as critical orchestrators of lung transplant tolerance and highlight the need to develop lung-specific immunosuppression.

Graphical Abstract
graphical abstract
Supplemental material

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View Supplemental Video 1. Graft-infiltrating recipient Foxp3+ cells interact with CD11c+ cells in tolerant lung allografts. Balb/c lungs, initially transplanted into CSB-treated B6 CD11c-EYFP mice and then at least 30 days later re-transplanted into non-immunosuppressed B6 Foxp3-IRES-GFP hosts were imaged with intravital two-photon microscopy three days after re-transplantation (n=3). CD11c+ cells within BALT are green and graft-infiltrating Foxp3+ cells are blue. Scale bar 20 μm. Circle depicts relevant cellular interactions. (GFP = green fluorescent protein, YFP = yellow fluorescent protein; rhodamine dextran labeling vessels red)

View Supplemental Video 2. Graft-infiltrating recipient Foxp3+ cells interact with graft-resident Foxp3+ cells in tolerant lung allografts. Balb/c lungs, initially transplanted into CSB-treated B6 Foxp3-IRES-GFP mice and then at least 30 days later re-transplanted into non-immunosuppressed B6.Foxp3-IRES-RFP recipients were imaged with intravital two-photon microscopy three days after re-transplantation (n=3). Graft-resident Foxp3+ cells are green and graft-infiltrating Foxp3+ cells are red. Scale bar 20 μm. Circle depicts relevant cellular interactions. (GFP = green fluorescent protein, RFP = red fluorescent protein)

View Supplemental Video 3. Graft-infiltrating recipient Foxp3+ cells interact with graft-infiltrating B cells in tolerant lung allografts. Balb/c lungs were initially transplanted into CSB-treated B6 CD11c-EYFP mice and then re-transplanted into non-immunosuppressed B6 Foxp3-IRES-GFP hosts at least 30 days later. Recipient-matched B6 CMTMR-labeled B cells were injected into recipients two days after re-transplantation and allografts were imaged with intravital two-photon microscopy the following day (n=4). CD11c+ cells within BALT are yellow, graft-infiltrating Foxp3+ cells are green and graft-infiltrating B cells are red. Scale bar 20 μm. Circle depicts relevant cellular interactions. (YFP = yellow fluorescent protein, GFP = green fluorescent protein, CMTMR = rhodamine-based red cell dye)

Version history
  • Version 1 (March 18, 2025): In-Press Preview
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