Adoptive Transfer with in Vitro Expanded Human Regulatory T Cells Protects Against Porcine Islet Xenograft Rejection Via Interleukin-10 in Humanized Mice

Overview

Journal Diabetes

Specialty Endocrinology

Date 2012 Mar 10

PMID 22403295

Citations 37

Authors

Shounan Yi

Ming Ji

Jingjing Wu

Xiaoqian Ma

Peta Phillips

Wayne J Hawthorne

Philip J OConnell

Affiliations

Soon will be listed here.

Abstract

T cell-mediated rejection remains a barrier to the clinical application of islet xenotransplantation. Regulatory T cells (Treg) regulate immune responses by suppressing effector T cells. This study aimed to determine the ability of human Treg to prevent islet xenograft rejection and the mechanism(s) involved. Neonatal porcine islet transplanted NOD-SCID IL2rγ(-/-) mice received human peripheral blood mononuclear cells (PBMC) with in vitro expanded autologous Treg in the absence or presence of anti-human interleukin-10 (IL-10) monoclonal antibody. In addition, human PBMC-reconstituted recipient mice received recombinant human IL-10 (rhIL-10). Adoptive transfer with expanded autologous Treg prevented islet xenograft rejection in human PBMC-reconstituted mice by inhibiting graft infiltration of effector cells and their function. Neutralization of human IL-10 shortened xenograft survival in mice receiving human PBMC and Treg. In addition, rhIL-10 treatment led to prolonged xenograft survival in human PBMC-reconstituted mice. This study demonstrates the ability of human Treg to prevent T-cell effector function and the importance of IL-10 in this response. In vitro Treg expansion was a simple and effective strategy for generating autologous Treg and highlighted a potential adoptive Treg cell therapy to suppress antigraft T-cell responses and reduce the requirement for immunosuppression in islet xenotransplantation.

Citing Articles

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References

Yi S, Hawthorne W, Lehnert A, Ha H, Wong J, van Rooijen N . T cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts. J Immunol. 2003; 170(5):2750-8. DOI: 10.4049/jimmunol.170.5.2750. View

Bacchetta R, Bigler M, Touraine J, Parkman R, Tovo P, Abrams J . High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med. 1994; 179(2):493-502. PMC: 2191349. DOI: 10.1084/jem.179.2.493. View

Wu J, Yi S, Ouyang L, Jimenez E, Simond D, Wang W . In vitro expanded human CD4+CD25+ regulatory T cells are potent suppressors of T-cell-mediated xenogeneic responses. Transplantation. 2008; 85(12):1841-8. DOI: 10.1097/TP.0b013e3181734793. View

Sakaguchi S . Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005; 6(4):345-52. DOI: 10.1038/ni1178. View

Brun V, Bastian H, Neveu V, Foussat A . Clinical grade production of IL-10 producing regulatory Tr1 lymphocytes for cell therapy of chronic inflammatory diseases. Int Immunopharmacol. 2009; 9(5):609-13. DOI: 10.1016/j.intimp.2009.01.032. View

Roohi Ahangarani R, Janssens W, Vanderelst L, Carlier V, VandenDriessche T, Chuah M . In vivo induction of type 1-like regulatory T cells using genetically modified B cells confers long-term IL-10-dependent antigen-specific unresponsiveness. J Immunol. 2009; 183(12):8232-43. DOI: 10.4049/jimmunol.0901777. View

Nagahama K, Nishimura E, Sakaguchi S . Induction of tolerance by adoptive transfer of Treg cells. Methods Mol Biol. 2007; 380:431-42. DOI: 10.1007/978-1-59745-395-0_27. View

Adeegbe D, Bayer A, Levy R, Malek T . Cutting edge: allogeneic CD4+CD25+Foxp3+ T regulatory cells suppress autoimmunity while establishing transplantation tolerance. J Immunol. 2006; 176(12):7149-53. DOI: 10.4049/jimmunol.176.12.7149. View

Cardona K, Korbutt G, Milas Z, Lyon J, Cano J, Jiang W . Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med. 2006; 12(3):304-6. DOI: 10.1038/nm1375. View

10.

Fiorina P, Shapiro A, Ricordi C, Secchi A . The clinical impact of islet transplantation. Am J Transplant. 2008; 8(10):1990-7. DOI: 10.1111/j.1600-6143.2008.02353.x. View

11.

Asseman C, Mauze S, Leach M, Coffman R, Powrie F . An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med. 1999; 190(7):995-1004. PMC: 2195650. DOI: 10.1084/jem.190.7.995. View

12.

Nadig S, Wieckiewicz J, Wu D, Warnecke G, Zhang W, Luo S . In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med. 2010; 16(7):809-13. PMC: 2929438. DOI: 10.1038/nm.2154. View

13.

Shultz L, Pearson T, King M, Giassi L, Carney L, Gott B . Humanized NOD/LtSz-scid IL2 receptor common gamma chain knockout mice in diabetes research. Ann N Y Acad Sci. 2007; 1103:77-89. DOI: 10.1196/annals.1394.002. View

14.

Issa F, Hester J, Goto R, Nadig S, Goodacre T, Wood K . Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model. Transplantation. 2010; 90(12):1321-7. PMC: 3672995. DOI: 10.1097/TP.0b013e3181ff8772. View

15.

Friedman T, Smith R, Colvin R, Iacomini J . A critical role for human CD4+ T-cells in rejection of porcine islet cell xenografts. Diabetes. 1999; 48(12):2340-8. DOI: 10.2337/diabetes.48.12.2340. View

16.

Korbutt G, Elliott J, Ao Z, Smith D, Warnock G, Rajotte R . Large scale isolation, growth, and function of porcine neonatal islet cells. J Clin Invest. 1996; 97(9):2119-29. PMC: 507287. DOI: 10.1172/JCI118649. View

17.

Wood K, Sakaguchi S . Regulatory T cells in transplantation tolerance. Nat Rev Immunol. 2003; 3(3):199-210. DOI: 10.1038/nri1027. View

18.

Sun L, Yi S, OConnell P . Foxp3 regulates human natural CD4+CD25+ regulatory T-cell-mediated suppression of xenogeneic response. Xenotransplantation. 2010; 17(2):121-30. DOI: 10.1111/j.1399-3089.2010.00571.x. View

19.

Sun L, Yi S, OConnell P . IL-10 is required for human CD4(+)CD25(+) regulatory T cell-mediated suppression of xenogeneic proliferation. Immunol Cell Biol. 2010; 88(4):477-85. DOI: 10.1038/icb.2009.117. View

20.

MacKenzie D, Hullett D, Sollinger H . Xenogeneic transplantation of porcine islets: an overview. Transplantation. 2003; 76(6):887-91. DOI: 10.1097/01.TP.0000087114.18315.17. View