Skip to main content
Top
Published in: Current Diabetes Reports 10/2019

01-10-2019 | Insulins | Immunology, Transplantation, and Regenerative Medicine (L Piemonti and V Sordi, Section Editors)

Targeting Stem Cell-Derived Tissue-Associated Regulatory T Cells for Type 1 Diabetes Immunotherapy

Authors: Mohammad Haque, Jugal Kishore Das, Xiaofang Xiong, Jianxun Song

Published in: Current Diabetes Reports | Issue 10/2019

Login to get access

Abstract

Purpose of Review

Type 1 diabetes (T1D) is an autoimmune disease in which the immune cells selectively destroy the pancreatic beta (β) cells and results in the deficiency of insulin production. The optimal treatment strategy for T1D should be preventing of β-cell destruction in the pancreas. The purpose of this review is to discuss the immunological therapeutic mechanisms that will help to understand the development and control of β-cell destruction. The review also presents a novel method for development of autoantigen (Ag)-specific regulatory T cells (Tregs) for T1D immunotherapy.

Recent Findings

Pancreatic-resident Tregs have the ability to dramatically suppress hyperactive immune cells. Islet cell transplantation is another attractive approach to replace the failed β cells. Due to the limited source of islet cells, research is going on in the use of animal cells and adult stem cells that may be derived from the patient’s own body to produce β cells for transplantation.

Summary

The mechanism behind the pancreatic β-cell destruction is largely unknown. In this review, a novel approach for the generation of tissue-associated Tregs from stem cells is considered. The stem cell-derived tissue-associated Tregs have the ability to home to the damaged pancreas to prevent the destruction. The review also provides new insights on the mechanism on how these suppressive immune cells protect the pancreas from the destruction of autoimmune cells. A novel method to develop functional auto Ag-specific Tregs that are derived from induced pluripotent stem cells (iPSCs), i.e., iPSC-Tregs, is discussed. Adoptive transfer of the iPSC-Tregs can substantially suppress T1D development in a murine model.
Literature
1.
go back to reference Beck J, Greenwood DA, Blanton L, Bollinger ST, Butcher MK, Condon JE, et al. 2017 national standards for diabetes self-management education and support. Diabetes Educ. 2019;45(1):34–49.PubMed Beck J, Greenwood DA, Blanton L, Bollinger ST, Butcher MK, Condon JE, et al. 2017 national standards for diabetes self-management education and support. Diabetes Educ. 2019;45(1):34–49.PubMed
2.
go back to reference Rariden C. Prediabetes: a wake-up call. Nursing. 2019;49(4):38–44.PubMed Rariden C. Prediabetes: a wake-up call. Nursing. 2019;49(4):38–44.PubMed
3.
go back to reference Egro FM. Why is type 1 diabetes increasing? J Mol Endocrinol. 2013;51(1):R1–13.PubMed Egro FM. Why is type 1 diabetes increasing? J Mol Endocrinol. 2013;51(1):R1–13.PubMed
4.
go back to reference James EA, Pietropaolo M, Mamula MJ. Immune recognition of beta-cells: neoepitopes as key players in the loss of tolerance. Diabetes. 2018;67(6):1035–42.PubMedPubMedCentral James EA, Pietropaolo M, Mamula MJ. Immune recognition of beta-cells: neoepitopes as key players in the loss of tolerance. Diabetes. 2018;67(6):1035–42.PubMedPubMedCentral
6.
go back to reference Yeh HC, Brown TT, Maruthur N, Ranasinghe P, Berger Z, Suh YD, et al. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med. 2012;157(5):336–47.PubMed Yeh HC, Brown TT, Maruthur N, Ranasinghe P, Berger Z, Suh YD, et al. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med. 2012;157(5):336–47.PubMed
7.
go back to reference • Spence A, Purtha W, Tam J, Dong S, Kim Y, Ju CH, et al. Revealing the specificity of regulatory T cells in murine autoimmune diabetes. Proc Natl Acad Sci U S A. 2018;115(20):5265–70. Findings from this study provide a glimpse into the specificities of Tregs in a natural repertoire that are crucial for opposing the progression of autoimmune diabetes. PubMedPubMedCentral • Spence A, Purtha W, Tam J, Dong S, Kim Y, Ju CH, et al. Revealing the specificity of regulatory T cells in murine autoimmune diabetes. Proc Natl Acad Sci U S A. 2018;115(20):5265–70. Findings from this study provide a glimpse into the specificities of Tregs in a natural repertoire that are crucial for opposing the progression of autoimmune diabetes. PubMedPubMedCentral
8.
go back to reference • Yu H, Gagliani N, Ishigame H, Huber S, Zhu S, Esplugues E, et al. Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development. Proc Natl Acad Sci U S A. 2017;114(39):10443–8. Findings from this study suggest that modulating gut-associated lymphoid tissue to boost Tr1 cells may be important in type 1 diabetes management.PubMedPubMedCentral • Yu H, Gagliani N, Ishigame H, Huber S, Zhu S, Esplugues E, et al. Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development. Proc Natl Acad Sci U S A. 2017;114(39):10443–8. Findings from this study suggest that modulating gut-associated lymphoid tissue to boost Tr1 cells may be important in type 1 diabetes management.PubMedPubMedCentral
9.
go back to reference Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity. 2008;28(6):870–80.PubMedPubMedCentral Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity. 2008;28(6):870–80.PubMedPubMedCentral
10.
go back to reference Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636–45.PubMed Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636–45.PubMed
11.
go back to reference Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198(12):1875–86.PubMedPubMedCentral Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198(12):1875–86.PubMedPubMedCentral
12.
go back to reference Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O'Shea JJ, et al. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med. 2008;205(9):1975–81.PubMedPubMedCentral Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O'Shea JJ, et al. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med. 2008;205(9):1975–81.PubMedPubMedCentral
13.
go back to reference Haque M, Fino K, Lei F, Xiong X, Song J. Utilizing regulatory T cells against rheumatoid arthritis. Front Oncol. 2014;4:209.PubMedPubMedCentral Haque M, Fino K, Lei F, Xiong X, Song J. Utilizing regulatory T cells against rheumatoid arthritis. Front Oncol. 2014;4:209.PubMedPubMedCentral
14.
go back to reference •• Haque M, Lei F, Xiong X, Das JK, Ren X, Fang D, et al. Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes. JCI Insight. 2019;4(7). Findings from this study suggest that the stemcell-derived tissue-associated Tregs can robustly accumulate in the diabetic pancreas, and, through downregulating the expression of ICAM-1 in the local inflamed tissues and inhibiting the production of proinflammatory cytokine IFN-γ, suppress the migration and activity of the pathogenic immune cells that cause T1D. •• Haque M, Lei F, Xiong X, Das JK, Ren X, Fang D, et al. Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes. JCI Insight. 2019;4(7). Findings from this study suggest that the stemcell-derived tissue-associated Tregs can robustly accumulate in the diabetic pancreas, and, through downregulating the expression of ICAM-1 in the local inflamed tissues and inhibiting the production of proinflammatory cytokine IFN-γ, suppress the migration and activity of the pathogenic immune cells that cause T1D.
15.
go back to reference Lei F, Haque R, Weiler L, Vrana KE, Song J. T lineage differentiation from induced pluripotent stem cells. Cell Immunol. 2009;260(1):1–5.PubMed Lei F, Haque R, Weiler L, Vrana KE, Song J. T lineage differentiation from induced pluripotent stem cells. Cell Immunol. 2009;260(1):1–5.PubMed
16.
go back to reference Lei F, Zhao B, Haque R, Xiong X, Budgeon L, Christensen ND, et al. In vivo programming of tumor antigen-specific T lymphocytes from pluripotent stem cells to promote cancer immunosurveillance. Cancer Res. 2011;71(14):4742–7.PubMed Lei F, Zhao B, Haque R, Xiong X, Budgeon L, Christensen ND, et al. In vivo programming of tumor antigen-specific T lymphocytes from pluripotent stem cells to promote cancer immunosurveillance. Cancer Res. 2011;71(14):4742–7.PubMed
17.
go back to reference Lei F, Haque R, Xiong X, Song J. Directed differentiation of induced pluripotent stem cells towards T lymphocytes. J Vis Exp. 2012;63:e3986. Lei F, Haque R, Xiong X, Song J. Directed differentiation of induced pluripotent stem cells towards T lymphocytes. J Vis Exp. 2012;63:e3986.
18.
go back to reference Haque R, Lei F, Xiong X, Bian Y, Zhao B, Wu Y, et al. Programming of regulatory T cells from pluripotent stem cells and prevention of autoimmunity. J Immunol. 2012;189(3):1228–36.PubMedPubMedCentral Haque R, Lei F, Xiong X, Bian Y, Zhao B, Wu Y, et al. Programming of regulatory T cells from pluripotent stem cells and prevention of autoimmunity. J Immunol. 2012;189(3):1228–36.PubMedPubMedCentral
19.
go back to reference Haque M, Song J, Fino K, Sandhu P, Song X, Lei F, et al. Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity. Sci Rep. 2016;6:20588.PubMedPubMedCentral Haque M, Song J, Fino K, Sandhu P, Song X, Lei F, et al. Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity. Sci Rep. 2016;6:20588.PubMedPubMedCentral
20.
go back to reference Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.
21.
go back to reference Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science. 2008;321(5889):699–702.PubMed Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science. 2008;321(5889):699–702.PubMed
22.
go back to reference • Lopez-Yrigoyen M, Yang CT, Fidanza A, Cassetta L, Taylor AH, McCahill A, et al. Genetic programming of macrophages generates an in vitro model for the human erythroid island niche. Nat Commun. 2019;10(1):881. Findings from this study suggest establishment of an in vitro system to model the human EI niche using macrophages that are derived from human iPSCs, and are also genetically programmed to an EI-like phenotype by inducible activation of the transcription factor, KLF1.PubMedPubMedCentral • Lopez-Yrigoyen M, Yang CT, Fidanza A, Cassetta L, Taylor AH, McCahill A, et al. Genetic programming of macrophages generates an in vitro model for the human erythroid island niche. Nat Commun. 2019;10(1):881. Findings from this study suggest establishment of an in vitro system to model the human EI niche using macrophages that are derived from human iPSCs, and are also genetically programmed to an EI-like phenotype by inducible activation of the transcription factor, KLF1.PubMedPubMedCentral
23.
go back to reference • Minagawa A, Yoshikawa T, Yasukawa M, Hotta A, Kunitomo M, Iriguchi S, et al. Enhancing T cell receptor stability in rejuvenated iPSC-derived T cells improves their use in cancer immunotherapy. Cell Stem Cell. 2018;23(6):850–8 e4. Findings from this study suggest that enhancing TCR stability in rejuvenated iPSC-derived T cells improves their use in cancer immunotherapy.PubMed • Minagawa A, Yoshikawa T, Yasukawa M, Hotta A, Kunitomo M, Iriguchi S, et al. Enhancing T cell receptor stability in rejuvenated iPSC-derived T cells improves their use in cancer immunotherapy. Cell Stem Cell. 2018;23(6):850–8 e4. Findings from this study suggest that enhancing TCR stability in rejuvenated iPSC-derived T cells improves their use in cancer immunotherapy.PubMed
24.
go back to reference Rezania A, Bruin JE, Riedel MJ, Mojibian M, Asadi A, Xu J, et al. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes. 2012;61(8):2016–29.PubMedPubMedCentral Rezania A, Bruin JE, Riedel MJ, Mojibian M, Asadi A, Xu J, et al. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes. 2012;61(8):2016–29.PubMedPubMedCentral
25.
go back to reference Kunisada Y, Tsubooka-Yamazoe N, Shoji M, Hosoya M. Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells. Stem Cell Res. 2012;8(2):274–84.PubMed Kunisada Y, Tsubooka-Yamazoe N, Shoji M, Hosoya M. Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells. Stem Cell Res. 2012;8(2):274–84.PubMed
26.
go back to reference Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 2008;26(11):1269–75.PubMed Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 2008;26(11):1269–75.PubMed
27.
go back to reference Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322(5903):949–53.PubMed Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322(5903):949–53.PubMed
28.
go back to reference Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26(4):443–52.PubMed Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26(4):443–52.PubMed
29.
go back to reference Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodriguez-Piza I, Vassena R, et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell. 2009;5(4):353–7.PubMedPubMedCentral Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodriguez-Piza I, Vassena R, et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell. 2009;5(4):353–7.PubMedPubMedCentral
30.
go back to reference Tateishi K, He J, Taranova O, Liang G, D'Alessio AC, Zhang Y. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem. 2008;283(46):31601–7.PubMed Tateishi K, He J, Taranova O, Liang G, D'Alessio AC, Zhang Y. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem. 2008;283(46):31601–7.PubMed
31.
go back to reference • Enderami SE, Mortazavi Y, Soleimani M, Nadri S, Biglari A, Mansour RN. Generation of insulin-producing cells from human-induced pluripotent stem cells using a stepwise differentiation protocol optimized with platelet-rich plasma. J Cell Physiol. 2017;232(10):2878–86. Findings from this study suggest a new approach to investigate the role of PRP in pancreatic differentiation protocols and enhance the feasibility of using patient-specific iPSCs and autologous PRP for future beta cells replacement therapies for T1DM.PubMed • Enderami SE, Mortazavi Y, Soleimani M, Nadri S, Biglari A, Mansour RN. Generation of insulin-producing cells from human-induced pluripotent stem cells using a stepwise differentiation protocol optimized with platelet-rich plasma. J Cell Physiol. 2017;232(10):2878–86. Findings from this study suggest a new approach to investigate the role of PRP in pancreatic differentiation protocols and enhance the feasibility of using patient-specific iPSCs and autologous PRP for future beta cells replacement therapies for T1DM.PubMed
32.
go back to reference Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A. 2009;106(37):15768–73.PubMedPubMedCentral Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A. 2009;106(37):15768–73.PubMedPubMedCentral
33.
go back to reference •• Millman JR, Xie C, Van Dervort A, Gurtler M, Pagliuca FW, Melton DA. Generation of stem cell-derived beta-cells from patients with type 1 diabetes. Nat Commun. 2016;7:11463 Findings from this study suggest that T1D SC-β cells could potentially be used for the treatment of diabetes, drug screening and the study of β-cell biology.PubMedPubMedCentral •• Millman JR, Xie C, Van Dervort A, Gurtler M, Pagliuca FW, Melton DA. Generation of stem cell-derived beta-cells from patients with type 1 diabetes. Nat Commun. 2016;7:11463 Findings from this study suggest that T1D SC-β cells could potentially be used for the treatment of diabetes, drug screening and the study of β-cell biology.PubMedPubMedCentral
34.
go back to reference Martin S, Pawlowski B, Greulich B, Ziegler AG, Mandrup-Poulsen T, Mahon J. Natural course of remission in IDDM during 1st yr after diagnosis. Diabetes Care. 1992;15(1):66–74.PubMed Martin S, Pawlowski B, Greulich B, Ziegler AG, Mandrup-Poulsen T, Mahon J. Natural course of remission in IDDM during 1st yr after diagnosis. Diabetes Care. 1992;15(1):66–74.PubMed
35.
go back to reference Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143–52.PubMedPubMedCentral Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143–52.PubMedPubMedCentral
36.
go back to reference Keymeulen B, Walter M, Mathieu C, Kaufman L, Gorus F, Hilbrands R, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia. 2010;53(4):614–23.PubMed Keymeulen B, Walter M, Mathieu C, Kaufman L, Gorus F, Hilbrands R, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia. 2010;53(4):614–23.PubMed
37.
go back to reference Gitelman SE, Gottlieb PA, Felner EI, Willi SM, Fisher LK, Moran A, et al. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia. 2016;59(6):1153–61.PubMedPubMedCentral Gitelman SE, Gottlieb PA, Felner EI, Willi SM, Fisher LK, Moran A, et al. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia. 2016;59(6):1153–61.PubMedPubMedCentral
38.
go back to reference Moran A, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381(9881):1905–15.PubMed Moran A, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381(9881):1905–15.PubMed
39.
go back to reference Takemoto N, Konagaya S, Kuwabara R, Iwata H. Coaggregates of regulatory T cells and islet cells allow long-term graft survival in liver without immunosuppression. Transplantation. 2015;99(5):942–7.PubMed Takemoto N, Konagaya S, Kuwabara R, Iwata H. Coaggregates of regulatory T cells and islet cells allow long-term graft survival in liver without immunosuppression. Transplantation. 2015;99(5):942–7.PubMed
40.
go back to reference Duggleby R, Danby RD, Madrigal JA, Saudemont A. Clinical grade regulatory CD4(+) T cells (Tregs): moving toward cellular-based immunomodulatory therapies. Front Immunol. 2018;9:252.PubMedPubMedCentral Duggleby R, Danby RD, Madrigal JA, Saudemont A. Clinical grade regulatory CD4(+) T cells (Tregs): moving toward cellular-based immunomodulatory therapies. Front Immunol. 2018;9:252.PubMedPubMedCentral
41.
go back to reference Marek-Trzonkowska N, Mysliwiec M, Iwaszkiewicz-Grzes D, Gliwinski M, Derkowska I, Zalinska M, et al. Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes. J Transl Med. 2016;14(1):332.PubMedPubMedCentral Marek-Trzonkowska N, Mysliwiec M, Iwaszkiewicz-Grzes D, Gliwinski M, Derkowska I, Zalinska M, et al. Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes. J Transl Med. 2016;14(1):332.PubMedPubMedCentral
42.
go back to reference Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189.PubMedPubMedCentral Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189.PubMedPubMedCentral
43.
go back to reference Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164(1):183–90.PubMed Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164(1):183–90.PubMed
44.
go back to reference • Boroughs AC, Larson RC, Choi BD, Bouffard AA, Riley LS, Schiferle E, et al. Chimeric antigen receptor costimulation domains modulate human regulatory T cell function. JCI Insight. 2019;5. Findings from this study suggest the use of CD28 based CAR-Tregs for tissue specific immune suppression in the clinic. • Boroughs AC, Larson RC, Choi BD, Bouffard AA, Riley LS, Schiferle E, et al. Chimeric antigen receptor costimulation domains modulate human regulatory T cell function. JCI Insight. 2019;5. Findings from this study suggest the use of CD28 based CAR-Tregs for tissue specific immune suppression in the clinic.
45.
go back to reference • Shimizu K, Iyoda T, Okada M, Yamasaki S, Fujii SI. Immune suppression and reversal of the suppressive tumor microenvironment. Int Immunol. 2018;30(10):445–54. Findings from this study suggest the new therapies that can reverse immune suppression in the TME and promote anti-tumorimmunity.PubMed • Shimizu K, Iyoda T, Okada M, Yamasaki S, Fujii SI. Immune suppression and reversal of the suppressive tumor microenvironment. Int Immunol. 2018;30(10):445–54. Findings from this study suggest the new therapies that can reverse immune suppression in the TME and promote anti-tumorimmunity.PubMed
46.
go back to reference Lim HW, Hillsamer P, Banham AH, Kim CH. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol. 2005;175(7):4180–3.PubMed Lim HW, Hillsamer P, Banham AH, Kim CH. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol. 2005;175(7):4180–3.PubMed
47.
go back to reference • Yoon J, Schmidt A, Zhang AH, Konigs C, Kim YC, Scott DW. FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T- and B-cell responses to FVIII. Blood. 2017;129(2):238–45. Findings from this study suggest that CAR-transduced Tregs are a promising approach for future tolerogenic treatment of hemophilia A patients with inhibitors.PubMedPubMedCentral • Yoon J, Schmidt A, Zhang AH, Konigs C, Kim YC, Scott DW. FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T- and B-cell responses to FVIII. Blood. 2017;129(2):238–45. Findings from this study suggest that CAR-transduced Tregs are a promising approach for future tolerogenic treatment of hemophilia A patients with inhibitors.PubMedPubMedCentral
48.
go back to reference Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;4(12):1206–12.PubMed Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;4(12):1206–12.PubMed
49.
go back to reference • Semitekolou M, Morianos I, Banos A, Konstantopoulos D, Adamou-Tzani M, Sparwasser T, et al. Dendritic cells conditioned by activin A-induced regulatory T cells exhibit enhanced tolerogenic properties and protect against experimental asthma. J Allergy Clin Immunol. 2018;141(2):671–84 e7. Findings from this study suggest that Act-A-iTreg cells instruct the generation of a highly effective immunoregulatory circuit encompassing tolerogenic DCs and forkhead box P3 + Treg cells that could be targeted for the design of novel immunotherapies for allergic disorders.PubMed • Semitekolou M, Morianos I, Banos A, Konstantopoulos D, Adamou-Tzani M, Sparwasser T, et al. Dendritic cells conditioned by activin A-induced regulatory T cells exhibit enhanced tolerogenic properties and protect against experimental asthma. J Allergy Clin Immunol. 2018;141(2):671–84 e7. Findings from this study suggest that Act-A-iTreg cells instruct the generation of a highly effective immunoregulatory circuit encompassing tolerogenic DCs and forkhead box P3 + Treg cells that could be targeted for the design of novel immunotherapies for allergic disorders.PubMed
50.
go back to reference Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A. 2007;104(49):19446–51.PubMedPubMedCentral Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A. 2007;104(49):19446–51.PubMedPubMedCentral
51.
go back to reference •• Guipouy D, Gertner-Dardenne J, Pfajfer L, German Y, Belmonte N, Dupre L. Granulysin- and granzyme-dependent elimination of myeloid cells by therapeutic ova-specific type 1 regulatory T cells. Int Immunol. 2019;31(4):239–50. Findings from this study suggest that ova-Tr1 cells are endowed with a sustained cytotoxic activity that relies on a unique combination of granulysin and granzymes and that preferentially eliminates myeloid target cells in a TCR-independent manner.PubMed •• Guipouy D, Gertner-Dardenne J, Pfajfer L, German Y, Belmonte N, Dupre L. Granulysin- and granzyme-dependent elimination of myeloid cells by therapeutic ova-specific type 1 regulatory T cells. Int Immunol. 2019;31(4):239–50. Findings from this study suggest that ova-Tr1 cells are endowed with a sustained cytotoxic activity that relies on a unique combination of granulysin and granzymes and that preferentially eliminates myeloid target cells in a TCR-independent manner.PubMed
52.
go back to reference Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12(4):431–40.PubMed Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12(4):431–40.PubMed
53.
go back to reference Aiello LP, Group DER. Diabetic retinopathy and other ocular findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37(1):17–23.PubMed Aiello LP, Group DER. Diabetic retinopathy and other ocular findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37(1):17–23.PubMed
54.
go back to reference Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum. 2005;52(7):2212–21.PubMed Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum. 2005;52(7):2212–21.PubMed
55.
go back to reference •• Sun G, Hou Y, Gong W, Liu S, Li J, Yuan Y, et al. Adoptive induced antigen-specific treg cells reverse inflammation in collagen-induced arthritis mouse model. Inflammation. 2018;41(2):485–95. Findings from this study suggest that adoptive induced antigen-specific Treg cells may have clinical applications for treatment of autoimmunity, including RA and other autoimmune disorders.PubMed •• Sun G, Hou Y, Gong W, Liu S, Li J, Yuan Y, et al. Adoptive induced antigen-specific treg cells reverse inflammation in collagen-induced arthritis mouse model. Inflammation. 2018;41(2):485–95. Findings from this study suggest that adoptive induced antigen-specific Treg cells may have clinical applications for treatment of autoimmunity, including RA and other autoimmune disorders.PubMed
56.
go back to reference Kohm AP, Carpentier PA, Anger HA, Miller SD. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol. 2002;169(9):4712–6.PubMed Kohm AP, Carpentier PA, Anger HA, Miller SD. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol. 2002;169(9):4712–6.PubMed
57.
go back to reference • Wilkinson DS, Ghosh D, Nickle RA, Moorman CD, Mannie MD. Partial CD25 antagonism enables dominance of antigen-inducible CD25(high) FOXP3(+) regulatory T cells as a basis for a regulatory T cell-based adoptive immunotherapy. Front Immunol. 2017;8:1782. Findings from this study suggest that low IL-2 concentrations coupled with high PC61 concentrations constrained IL-2 signaling to a low-intensity range that enabled dominant stable outgrowth of suppressive CD25 high FOXP3 + Tregs. The ability to indefinitely expand stable Treg lines will provide insight into FOXP3 + Treg physiology and will be foundational for Treg-based immunotherapy.PubMedPubMedCentral • Wilkinson DS, Ghosh D, Nickle RA, Moorman CD, Mannie MD. Partial CD25 antagonism enables dominance of antigen-inducible CD25(high) FOXP3(+) regulatory T cells as a basis for a regulatory T cell-based adoptive immunotherapy. Front Immunol. 2017;8:1782. Findings from this study suggest that low IL-2 concentrations coupled with high PC61 concentrations constrained IL-2 signaling to a low-intensity range that enabled dominant stable outgrowth of suppressive CD25 high FOXP3 + Tregs. The ability to indefinitely expand stable Treg lines will provide insight into FOXP3 + Treg physiology and will be foundational for Treg-based immunotherapy.PubMedPubMedCentral
58.
go back to reference Scalapino KJ, Tang Q, Bluestone JA, Bonyhadi ML, Daikh DI. Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J Immunol. 2006;177(3):1451–9.PubMed Scalapino KJ, Tang Q, Bluestone JA, Bonyhadi ML, Daikh DI. Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J Immunol. 2006;177(3):1451–9.PubMed
59.
go back to reference • Yang D, Tian Z, Zhang M, Yang W, Tang J, Wu Y, et al. NKG2D(+)CD4(+) T cells kill regulatory T cells in a NKG2D-NKG2D ligand-dependent manner in systemic lupus erythematosus. Sci Rep. 2017;7(1):1288 Findings from this study suggest that NKG2D +CD4 + T cells are involved in the pathogenesis of SLE by killing Treg cells in a NKG2D-NKG2DL-dependentmanner. Targeting the NKG2D-NKG2DL interaction might be a potential therapeutic strategy by which Treg cells can be protected from cytolysis in SLE patients.PubMedPubMedCentral • Yang D, Tian Z, Zhang M, Yang W, Tang J, Wu Y, et al. NKG2D(+)CD4(+) T cells kill regulatory T cells in a NKG2D-NKG2D ligand-dependent manner in systemic lupus erythematosus. Sci Rep. 2017;7(1):1288 Findings from this study suggest that NKG2D +CD4 + T cells are involved in the pathogenesis of SLE by killing Treg cells in a NKG2D-NKG2DL-dependentmanner. Targeting the NKG2D-NKG2DL interaction might be a potential therapeutic strategy by which Treg cells can be protected from cytolysis in SLE patients.PubMedPubMedCentral
60.
go back to reference Menetrier-Caux C, Gobert M, Caux C. Differences in tumor regulatory T-cell localization and activation status impact patient outcome. Cancer Res. 2009;69(20):7895–8.PubMed Menetrier-Caux C, Gobert M, Caux C. Differences in tumor regulatory T-cell localization and activation status impact patient outcome. Cancer Res. 2009;69(20):7895–8.PubMed
61.
go back to reference Hutmacher C, Gonzalo Nunez N, Liuzzi AR, Becher B, Neri D. Targeted delivery of IL2 to the tumor stroma potentiates the action of immune checkpoint inhibitors by preferential activation of NK and CD8(+) T cells. Cancer Immunol Res. 2019;7(4):572–83.PubMed Hutmacher C, Gonzalo Nunez N, Liuzzi AR, Becher B, Neri D. Targeted delivery of IL2 to the tumor stroma potentiates the action of immune checkpoint inhibitors by preferential activation of NK and CD8(+) T cells. Cancer Immunol Res. 2019;7(4):572–83.PubMed
62.
go back to reference Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006;7(1):83–92.PubMed Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006;7(1):83–92.PubMed
63.
go back to reference • Seitz C, Liu S, Klocke K, Joly AL, Czarnewski PV, Tibbitt CA, et al. Multi-faceted inhibition of dendritic cell function by CD4(+)Foxp3(+) regulatory T cells. J Autoimmun. 2019;98:86–94. Findings from this study suggest that Treg cells induced a specific immunosuppressive program in DCs.PubMed • Seitz C, Liu S, Klocke K, Joly AL, Czarnewski PV, Tibbitt CA, et al. Multi-faceted inhibition of dendritic cell function by CD4(+)Foxp3(+) regulatory T cells. J Autoimmun. 2019;98:86–94. Findings from this study suggest that Treg cells induced a specific immunosuppressive program in DCs.PubMed
64.
go back to reference Sarween N, Chodos A, Raykundalia C, Khan M, Abbas AK, Walker LS. CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion. J Immunol. 2004;173(5):2942–51.PubMed Sarween N, Chodos A, Raykundalia C, Khan M, Abbas AK, Walker LS. CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion. J Immunol. 2004;173(5):2942–51.PubMed
65.
go back to reference Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where CD4+CD25+ Treg cells impinge on autoimmune diabetes. J Exp Med. 2005;202(10):1387–97.PubMedPubMedCentral Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where CD4+CD25+ Treg cells impinge on autoimmune diabetes. J Exp Med. 2005;202(10):1387–97.PubMedPubMedCentral
66.
go back to reference •• Zou J, Gao X, Liu T, Liang R, Liu Y, Wang G, et al. Ethylenecarbodiimide-fixed splenocytes carrying whole islet antigens decrease the incidence of diabetes in NOD mice via down-regulation of effector memory T cells and autoantibodies. Endocr J. 2018;65(9):943–52. Findings from this study suggest that ECDI-fixed splenocytes carrying whole isletantigens effectively prevented the onset of T1DM in NOD mice, via suppressing the production of autoantibodies and inducing anergy of autoreactive T cells.PubMed •• Zou J, Gao X, Liu T, Liang R, Liu Y, Wang G, et al. Ethylenecarbodiimide-fixed splenocytes carrying whole islet antigens decrease the incidence of diabetes in NOD mice via down-regulation of effector memory T cells and autoantibodies. Endocr J. 2018;65(9):943–52. Findings from this study suggest that ECDI-fixed splenocytes carrying whole isletantigens effectively prevented the onset of T1DM in NOD mice, via suppressing the production of autoantibodies and inducing anergy of autoreactive T cells.PubMed
67.
go back to reference Roncarolo MG, Battaglia M, Gregori S. The role of interleukin 10 in the control of autoimmunity. J Autoimmun. 2003;20(4):269–72.PubMed Roncarolo MG, Battaglia M, Gregori S. The role of interleukin 10 in the control of autoimmunity. J Autoimmun. 2003;20(4):269–72.PubMed
68.
go back to reference •• Abdel-Latif M, Abdel-Moneim AA, El-Hefnawy MH, Khalil RG. Comparative and correlative assessments of cytokine, complement and antibody patterns in paediatric type 1 diabetes. Clin Exp Immunol. 2017;190(1):110–21. Findings from this study suggest that IFN-γ, IL-12 and IL-17 played an essential role in exacerbating EV +-T1D, while C3d, sC5b-9, IL-10 and -20 displayed distinct patterns.PubMedPubMedCentral •• Abdel-Latif M, Abdel-Moneim AA, El-Hefnawy MH, Khalil RG. Comparative and correlative assessments of cytokine, complement and antibody patterns in paediatric type 1 diabetes. Clin Exp Immunol. 2017;190(1):110–21. Findings from this study suggest that IFN-γ, IL-12 and IL-17 played an essential role in exacerbating EV +-T1D, while C3d, sC5b-9, IL-10 and -20 displayed distinct patterns.PubMedPubMedCentral
69.
go back to reference Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci U S A. 2004;101(13):4572–7.PubMedPubMedCentral Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci U S A. 2004;101(13):4572–7.PubMedPubMedCentral
70.
go back to reference • Kuhn C, Rezende RM, da Cunha AP, Valette F, Quintana FJ, Chatenoud L, et al. Mucosal administration of CD3-specific monoclonal antibody inhibits diabetes in NOD mice and in a preclinical mouse model transgenic for the CD3 epsilon chain. J Autoimmun. 2017;76:115–22. Findings from this study suggest that oral CD3-specific mAb has the potential for treating autoimmune diabetes in humans.PubMed • Kuhn C, Rezende RM, da Cunha AP, Valette F, Quintana FJ, Chatenoud L, et al. Mucosal administration of CD3-specific monoclonal antibody inhibits diabetes in NOD mice and in a preclinical mouse model transgenic for the CD3 epsilon chain. J Autoimmun. 2017;76:115–22. Findings from this study suggest that oral CD3-specific mAb has the potential for treating autoimmune diabetes in humans.PubMed
71.
go back to reference Battaglia M, Stabilini A, Draghici E, Migliavacca B, Gregori S, Bonifacio E, et al. Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes. 2006;55(6):1571–80.PubMed Battaglia M, Stabilini A, Draghici E, Migliavacca B, Gregori S, Bonifacio E, et al. Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes. 2006;55(6):1571–80.PubMed
72.
go back to reference Dai B, Wang P. In vitro differentiation of adult bone marrow progenitors into antigen-specific CD4 helper T cells using engineered stromal cells expressing a notch ligand and a major histocompatibility complex class II protein. Stem Cells Dev. 2009;18(2):235–45.PubMedPubMedCentral Dai B, Wang P. In vitro differentiation of adult bone marrow progenitors into antigen-specific CD4 helper T cells using engineered stromal cells expressing a notch ligand and a major histocompatibility complex class II protein. Stem Cells Dev. 2009;18(2):235–45.PubMedPubMedCentral
73.
go back to reference • Haque R, Song J, Haque M, Lei F, Sandhu P, Ni B, et al. c-Myc-induced survivin is essential for promoting the notch-dependent T cell differentiation from hematopoietic stem cells. Genes (Basel). 2017;8(3). Findings from this study suggest both c-Myc and survivin as important mediators of the Notch signaling-regulated differentiation of T lymphocytes from hematopoietic stem cells.PubMedCentral • Haque R, Song J, Haque M, Lei F, Sandhu P, Ni B, et al. c-Myc-induced survivin is essential for promoting the notch-dependent T cell differentiation from hematopoietic stem cells. Genes (Basel). 2017;8(3). Findings from this study suggest both c-Myc and survivin as important mediators of the Notch signaling-regulated differentiation of T lymphocytes from hematopoietic stem cells.PubMedCentral
74.
go back to reference Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, et al. Stability of the regulatory T cell lineage in vivo. Science. 2010;329(5999):1667–71.PubMedPubMedCentral Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, et al. Stability of the regulatory T cell lineage in vivo. Science. 2010;329(5999):1667–71.PubMedPubMedCentral
75.
go back to reference Kurts C, Heath WR, Carbone FR, Allison J, Miller JF, Kosaka H. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J Exp Med. 1996;184(3):923–30.PubMed Kurts C, Heath WR, Carbone FR, Allison J, Miller JF, Kosaka H. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J Exp Med. 1996;184(3):923–30.PubMed
Metadata
Title
Targeting Stem Cell-Derived Tissue-Associated Regulatory T Cells for Type 1 Diabetes Immunotherapy
Authors
Mohammad Haque
Jugal Kishore Das
Xiaofang Xiong
Jianxun Song
Publication date
01-10-2019
Publisher
Springer US
Published in
Current Diabetes Reports / Issue 10/2019
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-019-1213-7

Other articles of this Issue 10/2019

Current Diabetes Reports 10/2019 Go to the issue

Other Forms of Diabetes and Its Complications (JJ Nolan and H Thabit, Section Editors)

Association Between Antipsychotic Medication Use and Diabetes

Obesity (KM Gadde, Section Editor)

Medical Devices in Obesity Treatment

Hospital Management of Diabetes (A Wallia and JJ Seley, Section Editors)

Inpatient Diabetes Education in the Real World: an Overview of Guidelines and Delivery Models

Therapies and New Technologies in the Treatment of Diabetes (M Pietropaolo, Section Editor)

Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia

Obesity (KM Gadde, Section Editor)

Predictive Mathematical Models of Weight Loss

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

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

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