Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2015

Open Access 01-12-2015 | Research

Foxp3-modified bone marrow mesenchymal stem cells promotes liver allograft tolerance through the generation of regulatory T cells in rats

Authors: Haizhi Qi, Guangshun Chen, Yaxun Huang, Zhongzhou Si, Jiequn Li

Published in: Journal of Translational Medicine | Issue 1/2015

Login to get access

Abstract

Background

The transcription factor forkhead box P3 (Foxp3) is a master regulatory gene necessary for the development and function of CD4+CD25+ regulatory T cells (Tregs). Mesenchymal stem cells (MSC) have recently emerged as promising candidates for cell-based immunosuppression/tolerance induction protocols. Thus, we hypothesized that MSC-based Foxp3 gene therapy would improve immunosuppressive capacity of MSC and induce donor-specific allograft tolerance in rat’s liver allograft model.

Methods

The present study utilized a lentivirus vector to overexpress the therapeutic gene Foxp3 on MSC. In vivo, Injections of 2 × 106 MSC, FUGW-MSC or Foxp3-MSC into the portal vein were carried out immediately after liver transplantation.

Results

Successful gene transfer of Foxp3 in MSC was achieved by lentivirus carrying Foxp3 and Foxp3-MSC engraftment in liver allograft was confirmed by fluorescence microscopy. Foxp3-MSC treatment significantly inhibited the proliferation of allogeneic ACI CD4+ T cells to splenocytes (SC) from the same donor strain or third-party BN rat compared with MSC. Foxp3-MSC suppressive effect on the proliferation of CD4+ T cells is contact dependent and associated with Programmed death ligand 1(PD-L1) upregulation in MSC. Co-culture of CD4+ T cells with Foxp3-MSC results in a shift towards a Tregs phenotype. More importantly, Foxp3-MSC monotherapy achieved donor-specific liver allograft tolerance and generated a state of CD4+CD25+Foxp3+ Tregs-dependent tolerance.

Conclusion

Foxp3-engineered MSC therapy seems to be a promising and attractive cell therapy approach for inducing immunosuppression or transplant tolerance.
Literature
1.
Long E, Wood KJ. Understanding FOXP3: progress towards achieving transplantation tolerance. Transplantation. 2007;84(4):459–61.CrossRefPubMed
2.
Lai Y, Drobinskaya I, Kolossov E, Chen C, Linn T. Genetic modification of cells for transplantation. Adv Drug Deliv Rev. 2008;60(2):146–59.CrossRefPubMed
3.
Park TG, Jeong JH, Kim SW. Current status of polymeric gene delivery systems. Adv Drug Deliv Rev. 2006;58(4):467–86.CrossRefPubMed
4.
Dalberto TP, Nardi NB, Camassola M. Mesenchymal stem cells as a platform for gene therapy protocols. Sci Prog. 2010;93(Pt 2):129–40.CrossRefPubMed
5.
Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol. 2006;36(10):2566–73.CrossRefPubMed
6.
Ozawa K, Sato K, Oh I, Ozaki K, Uchibori R, Obara Y, et al. Cell and gene therapy using mesenchymal stem cells (MSCs). J Autoimmun. 2008;30(3):121–7.CrossRefPubMed
7.
Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008;181(6):3933–46.CrossRefPubMed
8.
Ge W, Jiang J, Baroja ML, Arp J, Zassoko R, Liu W, et al. Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am J Transplant. 2009;9(8):1760–72.CrossRefPubMed
9.
Wang Y, Zhang A, Ye Z, Xie H, Zheng S. Bone marrow-derived mesenchymal stem cells inhibit acute rejection of rat liver allografts in association with regulatory T-cell expansion. Transplant Proc. 2009;41(10):4352–6.CrossRefPubMed
10.
Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57(1):11–20.CrossRefPubMed
11.
Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30(1):42–8.CrossRefPubMed
12.
Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation. 2010;90(12):1312–20.CrossRefPubMed
13.
Borg DJ, Weigelt M, Wilhelm C, Gerlach M, Bickle M, Speier S, et al. Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model. Diabetologia. 2014;57(3):522–31.CrossRefPubMed
14.
Reinders ME, de Fijter JW, Roelofs H, Bajema IM, de Vries DK, Schaapherder AF, et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med. 2012;2(2):107–11.CrossRef
15.
Casiraghi F, Azzollini N, Todeschini M, Cavinato RA, Cassis P, Solini S, et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant. 2012;12(9):2373–83.CrossRefPubMed
16.
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371(9624):1579–86.CrossRefPubMed
17.
Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol. 2003;3(3):199–210.CrossRefPubMed
18.
Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.CrossRefPubMed
19.
Feng G, Wood KJ, Bushell A. Interferon-gamma conditioning ex vivo generates CD25+ CD62L+ Foxp3+ regulatory T cells that prevent allograft rejection: potential avenues for cellular therapy. Transplantation. 2008;86(4):578–89.CrossRefPubMed
20.
Graca L, Le Moine A, Lin CY, Fairchild PJ, Cobbold SP, Waldmann H. Donor-specific transplantation tolerance: the paradoxical behavior of CD4+ CD25+ T cells. Proc Natl Acad Sci USA. 2004;101(27):10122–6.PubMedCentralCrossRefPubMed
21.
Fan Z, Spencer JA, Lu Y, Pitsillides CM, Singh G, Kim P, et al. In vivo tracking of ‘color-coded’ effector, natural and induced regulatory T cells in the allograft response. Nat Med. 2010;16(6):718–22.PubMedCentralCrossRefPubMed
22.
Lee I, Wang L, Wells AD, Dorf ME, Ozkaynak E, Hancock WW. Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med. 2005;201(7):1037–44.PubMedCentralCrossRefPubMed
23.
Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, et al. Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol. 2004;172(10):6003–10.CrossRefPubMed
24.
Turnquist HR, Raimondi G, Zahorchak AF, Fischer RT, Wang Z, Thomson AW. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance. J Immunol. 2007;178(11):7018–31.CrossRefPubMed
25.
Kendal AR, Chen Y, Regateiro FS, Ma J, Adams E, Cobbold SP, et al. Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance. J Exp Med. 2011;208(10):2043–53.PubMedCentralCrossRefPubMed
26.
27.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.CrossRefPubMed
28.
Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S, et al. Crucial role of FOXP3 in the development and function of human CD25+ CD4+ regulatory T cells. Int Immunol. 2004;16(11):1643–56.CrossRefPubMed
29.
Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature. 2007;445(7130):931–5.PubMedCentralCrossRefPubMed
30.
Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 2007;445(7130):936–40.CrossRefPubMed
31.
Inoue S, Popp FC, Koehl GE, Piso P, Schlitt HJ, Geissler EK, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation. 2006;81(11):1589–95.CrossRefPubMed
32.
Popp FC, Eggenhofer E, Renner P, Slowik P, Lang SA, Kaspar H, et al. Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. Transpl Immunol. 2008;20(1–2):55–60.CrossRefPubMed
33.
Kamada N, Calne RY. A surgical experience with five hundred thirty liver transplants in the rat. Surgery. 1983;93(1 Pt 1):64–9.PubMed
34.
Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.CrossRefPubMed
35.
Horoldt BS, Burattin M, Gunson BK, Bramhall SR, Nightingale P, Hubscher SG, et al. Does the Banff rejection activity index predict outcome in patients with early acute cellular rejection following liver transplantation? Liver Transpl. 2006;12(7):1144–51.CrossRefPubMed
36.
Demetris AJBK, Dhillon AP. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology. 1997;25(3):658–63.CrossRef
37.
Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007;445(7129):766–70.CrossRefPubMed
38.
Hoogduijn MJ, Popp FC, Grohnert A, Crop MJ, van Rhijn M, Rowshani AT, et al. Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT). Transplantation. 2010;90(2):124–6.CrossRefPubMed
39.
Eggenhofer E, Steinmann JF, Renner P, Slowik P, Piso P, Geissler EK, et al. Mesenchymal stem cells together with mycophenolate mofetil inhibit antigen presenting cell and T cell infiltration into allogeneic heart grafts. Transpl Immunol. 2011;24(3):157–63.CrossRefPubMed
40.
Min CK, Kim BG, Park G, Cho B, Oh IH. IL-10-transduced bone marrow mesenchymal stem cells can attenuate the severity of acute graft-versus-host disease after experimental allogeneic stem cell transplantation. Bone Marrow Transplant. 2007;39(10):637–45.CrossRefPubMed
41.
Bian L, Guo ZK, Wang HX, Wang JS, Wang H, Li QF, et al. In vitro and in vivo immunosuppressive characteristics of hepatocyte growth factor-modified murine mesenchymal stem cells. Vivo. 2009;23(1):21–7.
42.
Li A, Zhang Q, Jiang J, Yuan G, Feng Y, Hao J, et al. Co-transplantation of bone marrow stromal cells transduced with IL-7 gene enhances immune reconstitution after allogeneic bone marrow transplantation in mice. Gene Ther. 2006;13(15):1178–87.CrossRefPubMed
43.
Kitagawa Y, Ohkura N, Sakaguchi S. Epigenetic control of thymic Treg-cell development. Eur J Immunol. 2015;45(1):11–6.CrossRefPubMed
44.
Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8(3):277–84.CrossRefPubMed
45.
Keir ME, Freeman GJ, Sharpe AH. PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J Immunol. 2007;179(8):5064–70.CrossRefPubMed
46.
Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4(5):336–47.CrossRefPubMed
47.
Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol. 2005;35(5):1482–90.CrossRefPubMed
48.
Kitazawa Y, Fujino M, Wang Q, Kimura H, Azuma M, Kubo M, et al. Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+ CD25+ regulatory T-cell activity to suppress alloimmune responses. Transplantation. 2007;83(6):774–82.CrossRefPubMed
49.
Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 2008;18(8):846–57.CrossRefPubMed
50.
Wang H, Qi F, Dai X, Tian W, Liu T, Han H, et al. Requirement of B7-H1 in mesenchymal stem cells for immune tolerance to cardiac allografts in combination therapy with rapamycin. Transpl Immunol. 2014;31(2):65–74.CrossRefPubMed
51.
Wang L, Han R, Hancock WW. Programmed cell death 1 (PD-1) and its ligand PD-L1 are required for allograft tolerance. Eur J Immunol. 2007;37(10):2983–90.CrossRefPubMed
52.
English K, Barry FP, Field-Corbett CP, Mahon BP. IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett. 2007;110(2):91–100.CrossRefPubMed
53.
Ghannam S, Pene J, Moquet-Torcy G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol. 2010;185(1):302–12.CrossRefPubMed
54.
Gur-Wahnon D, Borovsky Z, Beyth S, Liebergall M, Rachmilewitz J. Contact-dependent induction of regulatory antigen-presenting cells by human mesenchymal stem cells is mediated via STAT3 signaling. Exp Hematol. 2007;35(3):426–33.CrossRefPubMed
55.
Burr SP, Dazzi F, Garden OA. Mesenchymal stromal cells and regulatory T cells: the Yin and Yang of peripheral tolerance? Immunol Cell Biol. 2013;91(1):12–8.CrossRefPubMed
56.
English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, Mahon BP. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+ CD25(High) forkhead box P3+ regulatory T cells. Clin Exp Immunol. 2009;156(1):149–60.PubMedCentralCrossRefPubMed
Metadata
Title
Foxp3-modified bone marrow mesenchymal stem cells promotes liver allograft tolerance through the generation of regulatory T cells in rats
Authors
Haizhi Qi
Guangshun Chen
Yaxun Huang
Zhongzhou Si
Jiequn Li
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2015
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-015-0638-2

Other articles of this Issue 1/2015

Journal of Translational Medicine 1/2015 Go to the issue

Research

Luteolin exerts a marked antitumor effect in cMet-overexpressing patient-derived tumor xenograft models of gastric cancer

Research

Analysis of multivariate longitudinal kidney function outcomes using generalized linear mixed models

Research

Case report of non-healing surgical wound treated with dehydrated human amniotic membrane

Research

Inhibition of human diffuse large B-cell lymphoma growth by JC polyomavirus-like particles delivering a suicide gene

Research

Interactions of tumour-derived micro(nano)vesicles with human gastric cancer cells

Research

Effect of the JAK2/STAT3 inhibitor SAR317461 on human glioblastoma tumorspheres
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits