Diabetologia

, Volume 60, Issue 12, pp 2418–2431 | Cite as

Multipeptide-coupled nanoparticles induce tolerance in ‘humanised’ HLA-transgenic mice and inhibit diabetogenic CD8+ T cell responses in type 1 diabetes

  • Xinyu Xu
  • Lingling Bian
  • Min Shen
  • Xin Li
  • Jing Zhu
  • Shuang Chen
  • Lei Xiao
  • Qingqing Zhang
  • Heng Chen
  • Kuanfeng Xu
  • Tao Yang
Article

Abstract

Aims/hypothesis

Induction of antigen-specific immunological tolerance may provide an attractive immunotherapy in the NOD mouse model but the conditions that lead to the successful translation to human type 1 diabetes are limited. In this study, we covalently linked 500 nm carboxylated polystyrene beads (PSB) with a mixture of immunodominant HLA-A*02:01-restricted epitopes (peptides-PSB) that may have high clinical relevance in humans as they promote immune tolerance; we then investigated the effect of the nanoparticle–peptide complexes on T cell tolerance.

Methods

PSB-coupled mixtures of HLA-A*02:01-restricted epitopes were administered to HHD II mice via intravenous injection. The effects on delaying the course of the disease were verified in NOD.β2mnull HHD mice. The diabetogenic HLA-A*02:01-restricted cytotoxic lymphocyte (CTL) responses to treatment with peptides-PSB were validated in individuals with type 1 diabetes.

Results

We showed that peptides-PSB could induce antigen-specific tolerance in HHD II mice. The protective immunological mechanisms were mediated through the function of CD4+CD25+ regulatory T cells, suppressive T cell activation and T cell anergy. Furthermore, the peptides-PSB induced an activation and accumulation of regulatory T cells and CD11c+ dendritic cells through a rapid production of CD169+ macrophage-derived C-C motif chemokine 22 (CCL22). Peptides-PSB also prevented diabetes in ‘humanised’ NOD.β2mnull HHD mice and suppressed pathogenic CTL responses in people with type 1 diabetes.

Conclusions/interpretation

Our findings demonstrate for the first time the potential for using multipeptide-PSB complexes to induce T cell tolerance and halt the autoimmune process. These findings represent a promising platform for an antigen-specific tolerance strategy in type 1 diabetes and highlight a mechanism through which metallophilic macrophages mediate the early cell–cell interactions required for peptides-PSB-induced immune tolerance.

Keywords

Antigen-specific tolerance Humanised mice Immunotherapy Nanoparticles Type 1 diabetes 

Abbreviations

Ag-SP

Antigen-conjugated apoptotic splenocyte

APC

Antigen-presenting cell

CCL22

C-C motif chemokine 22

CCR4

C-C chemokine receptor type 4

CFA

Complete Freund’s adjuvant

CFSE

Carboxyfluorescein diacetate succinimidyl ester

CMV

Cytomegalovirus

CTL

Cytotoxic lymphocyte

DC

Dendritic cell

ECDI

Ethylene carbodiimide

HIV

Human immunodeficiency virus

IFA

Incomplete Freund’s adjuvant

IGRP

Islet-specific glucose-6-phosphatase catalytic subunit-related protein

MARCO

Macrophage receptor with collagenous structure

Macrophage

MMΦ

Metallophilic macrophage

MZ

Marginal zone

MZMΦ

Marginal zone macrophage

PBMC

Peripheral blood mononuclear cells

PSB

Polystyrene beads

SFC

Spot-forming cells

Th

T helper

Treg

Regulatory T cell

ZnT8

Zinc transporter-8

Supplementary material

125_2017_4419_MOESM1_ESM.pdf (2.4 mb)
ESM(PDF 2420 kb)

References

  1. 1.
    Coppieters KT, Dotta F, Amirian N et al (2012) Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 209:51–60CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Carbone J, del Pozo N, Gallego A, Sarmiento E (2011) Immunological risk factors for infection after immunosuppressive and biologic therapies. Expert Rev Anti-Infect Ther 9:405–413CrossRefPubMedGoogle Scholar
  3. 3.
    Riminton DS, Hartung HP, Reddel SW (2011) Managing the risks of immunosuppression. Curr Opin Neurol 24:217–223CrossRefPubMedGoogle Scholar
  4. 4.
    Luo X, Herold KC, Miller SD (2010) Immunotherapy of type 1 diabetes: where are we and where should we be going? Immunity 32:488–499CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Orban T, Farkas K, Jalahej H et al (2010) Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy. J Autoimmun 34:408–415CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Daniel C, Weigmann B, Bronson R, von Boehmer H (2011) Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope. J Exp Med 208:1501–1510CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Han B, Serra P, Amrani A et al (2005) Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide. Nat Med 11:645–652CrossRefPubMedGoogle Scholar
  8. 8.
    Wherrett DK, Bundy B, Becker DJ et al (2011) Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 378:319–327CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bluestone JA, Bour-Jordan H (2012) Current and future immunomodulation strategies to restore tolerance in autoimmune diseases. Cold Spring Harb Perspect Biol 4:a007542CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Prasad S, Xu D, Miller SD (2012) Tolerance strategies employing antigen-coupled apoptotic cells and carboxylated PLG nanoparticles for the treatment of type 1 diabetes. Rev Diabet Stud 9:319–327CrossRefPubMedGoogle Scholar
  11. 11.
    Miller SD, Turley DM, Podojil JR (2007) Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat Rev Immunol 7:665–677CrossRefPubMedGoogle Scholar
  12. 12.
    Smith CE, Miller SD (2006) Multi-peptide coupled-cell tolerance ameliorates ongoing relapsing EAE associated with multiple pathogenic autoreactivity. J Autoimmun 27:218–231CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Niens M, Grier AE, Marron M, Kay TW, Greiner DL, Serreze DV (2011) Prevention of “humanized” diabetogenic CD8 T cell responses in HLA-transgenic NOD mice by a multipeptide coupled-cell approach. Diabetes 60:1229–1236CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Smith CE, Eagar TN, Strominger JL, Miller SD (2005) Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 102:9595–9600CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lutterotti A, Yousef S, Sputtek A et al (2013) Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis. Sci Transl Med 5:188ra175CrossRefGoogle Scholar
  16. 16.
    Getts DR, Martin AJ, McCarthy DP et al (2012) Microparticles bearing encephalitogenic peptides induce T cell tolerance and ameliorate experimental autoimmune encephalomyelitis. Nat Biotechnol 30:1217–1224CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Maldonado RA, LaMothe RA, Ferrari JD et al (2015) Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc Natl Acad Sci U S A 112:E156–E165CrossRefPubMedGoogle Scholar
  18. 18.
    Hlavaty KA, McCarthy DP, Saito E, Yap WT, Miller SD, Shea LD (2016) Tolerance induction using nanoparticles bearing HY peptides in bone marrow transplantation. Biomaterials 76:1–10CrossRefPubMedGoogle Scholar
  19. 19.
    Smarr CB, Yap WT, Neef TP et al (2016) Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization. Proc Natl Acad Sci U S A 113:5059–5064CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tyner K, Sadrieh N (2011) Considerations when submitting nanotherapeutics to FDA/CDER for regulatory review. Methods Mol Biol 697:17–31CrossRefPubMedGoogle Scholar
  21. 21.
    ADA (2013) Diagnosis and classification of diabetes mellitus. Diabetes Care 36(Suppl 1):S67–S74Google Scholar
  22. 22.
    Pascolo S, Bervas N, Ure JM, Smith AG, Lemonnier FA, Perarnau B (1997) HLA-A2.1-restricted education and cytolytic activity of CD8(+) T lymphocytes from beta2 microglobulin (beta2m) HLA-A2.1 monochain transgenic H-2Db beta2m double knockout mice. J Exp Med 185:2043–2051CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Takaki T, Marron MP, Mathews CE et al (2006) HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 176:3257–3265CrossRefPubMedGoogle Scholar
  24. 24.
    Penaranda C, Kuswanto W, Hofmann J et al (2012) IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells. Proc Natl Acad Sci U S A 109:12668–12673CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lasch S, Muller P, Bayer M et al (2015) Anti-CD3/anti-CXCL10 antibody combination therapy induces a persistent remission of type 1 diabetes in two mouse models. Diabetes 64:4198–4211CrossRefPubMedGoogle Scholar
  26. 26.
    Xu X, Gu Y, Bian L et al (2016) Characterization of immune response to novel HLA-A2-restricted epitopes from zinc transporter 8 in type 1 diabetes. Vaccine 34:854–862CrossRefPubMedGoogle Scholar
  27. 27.
    McGaha TL, Karlsson MC (2016) Apoptotic cell responses in the splenic marginal zone: a paradigm for immunologic reactions to apoptotic antigens with implications for autoimmunity. Immunol Rev 269:26–43CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Borges da Silva H, Fonseca R, Pereira RM, Cassado Ados A, Alvarez JM, D'Imperio Lima MR (2015) Splenic macrophage subsets and their function during blood-borne infections. Front Immunol 6:480CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ravishankar B, McGaha TL (2013) O death where is thy sting? Immunologic tolerance to apoptotic self. Cell Mol Life Sci 70:3571–3589CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yamashita U, Kuroda E (2002) Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit Rev Immunol 22:105–114CrossRefPubMedGoogle Scholar
  31. 31.
    Gobert M, Treilleux I, Bendriss-Vermare N et al (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69:2000–2009CrossRefPubMedGoogle Scholar
  32. 32.
    Ravishankar B, Shinde R, Liu H et al (2014) Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc Natl Acad Sci U S A 111:4215–4220CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Chow Z, Mueller SN, Deane JA, Hickey MJ (2013) Dermal regulatory T cells display distinct migratory behavior that is modulated during adaptive and innate inflammation. J Immunol 191:3049–3056CrossRefPubMedGoogle Scholar
  34. 34.
    Scott CL, Aumeunier AM, Mowat AM (2011) Intestinal CD103+ dendritic cells: master regulators of tolerance? Trends Immunol 32:412–419CrossRefPubMedGoogle Scholar
  35. 35.
    Belkaid Y, Oldenhove G (2008) Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity 29:362–371CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Getts DR, Shea LD, Miller SD, King NJ (2015) Harnessing nanoparticles for immune modulation. Trends Immunol 36:419–427CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Judkowski V, Rodriguez E, Pinilla C et al (2004) Peptide specific amelioration of T cell mediated pathogenesis in murine type 1 diabetes. Clin Immunol 113:29–37CrossRefPubMedGoogle Scholar
  38. 38.
    Lieberman SM, Evans AM, Han B et al (2003) Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci U S A 100:8384–8388CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Irvine DJ, Swartz MA, Szeto GL (2013) Engineering synthetic vaccines using cues from natural immunity. Nat Mater 12:978–990CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Metcalfe SM, Fahmy TM (2012) Targeted nanotherapy for induction of therapeutic immune responses. Trends Mol Med 18:72–80CrossRefPubMedGoogle Scholar
  41. 41.
    McGaha TL, Chen Y, Ravishankar B, van Rooijen N, Karlsson MC (2011) Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen. Blood 117:5403–5412CrossRefPubMedGoogle Scholar
  42. 42.
    Iyoda T, Shimoyama S, Liu K et al (2002) The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 195:1289–1302CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Liu K, Iyoda T, Saternus M, Kimura Y, Inaba K, Steinman RM (2002) Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 196:1091–1097CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Godiska R, Chantry D, Raport CJ et al (1997) Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells. J Exp Med 185:1595–1604CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Pere H, Montier Y, Bayry J et al (2011) A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens. Blood 118:4853–4862CrossRefPubMedGoogle Scholar
  46. 46.
    Poppensieker K, Otte DM, Schurmann B et al (2012) CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells. Proc Natl Acad Sci U S A 109:3897–3902CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Evers BD, Engel DR, Bohner AM et al (2016) CD103+ kidney dendritic cells protect against crescentic GN by maintaining IL-10-producing regulatory T cells. J Am Soc Nephrol 27:3368–3382CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Oeser JK, Parekh VV, Wang Y et al (2011) Deletion of the G6pc2 gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein does not affect the progression or incidence of type 1 diabetes in NOD/ShiLtJ mice. Diabetes 60:2922–2927CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Krishnamurthy B, Dudek NL, McKenzie MD et al (2006) Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest 116:3258–3265CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Xinyu Xu
    • 1
  • Lingling Bian
    • 1
    • 2
  • Min Shen
    • 1
  • Xin Li
    • 1
  • Jing Zhu
    • 1
  • Shuang Chen
    • 1
  • Lei Xiao
    • 1
  • Qingqing Zhang
    • 1
  • Heng Chen
    • 1
  • Kuanfeng Xu
    • 1
  • Tao Yang
    • 1
  1. 1.Department of EndocrinologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingPeople’s Republic of China
  2. 2.Department of EndocrinologyYancheng City No.1 People’s HospitalYanchengPeople’s Republic of China

Personalised recommendations