nach oben

Erschienen in:

08.09.2017 | Article

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

verfasst von: Xinyu Xu, Lingling Bian, Min Shen, Xin Li, Jing Zhu, Shuang Chen, Lei Xiao, Qingqing Zhang, Heng Chen, Kuanfeng Xu, Tao Yang

Erschienen in: Diabetologia | Ausgabe 12/2017

Einloggen, um Zugang zu erhalten

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.β2m ^null 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.β2m ^null 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.

Nur mit Berechtigung zugänglich

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 209:51–60CrossRefPubMedPubMedCentral

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 9:405–413CrossRefPubMed

Riminton DS, Hartung HP, Reddel SW (2011) Managing the risks of immunosuppression. Curr Opin Neurol 24:217–223CrossRefPubMed

Luo X, Herold KC, Miller SD (2010) Immunotherapy of type 1 diabetes: where are we and where should we be going? Immunity 32:488–499CrossRefPubMedPubMedCentral

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 34:408–415CrossRefPubMedPubMedCentral

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 208:1501–1510CrossRefPubMedPubMedCentral

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 11:645–652CrossRefPubMed

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 378:319–327CrossRefPubMedPubMedCentral

Bluestone JA, Bour-Jordan H (2012) Current and future immunomodulation strategies to restore tolerance in autoimmune diseases. Cold Spring Harb Perspect Biol 4:a007542CrossRefPubMedPubMedCentral

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 9:319–327CrossRefPubMed

11.

Miller SD, Turley DM, Podojil JR (2007) Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat Rev Immunol 7:665–677CrossRefPubMed

12.

Smith CE, Miller SD (2006) Multi-peptide coupled-cell tolerance ameliorates ongoing relapsing EAE associated with multiple pathogenic autoreactivity. J Autoimmun 27:218–231CrossRefPubMedPubMedCentral

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 60:1229–1236CrossRefPubMedPubMedCentral

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 102:9595–9600CrossRefPubMedPubMedCentral

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 5:188ra175CrossRef

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 30:1217–1224CrossRefPubMedPubMedCentral

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–E165CrossRefPubMed

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 76:1–10CrossRefPubMed

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 113:5059–5064CrossRefPubMedPubMedCentral

20.

Tyner K, Sadrieh N (2011) Considerations when submitting nanotherapeutics to FDA/CDER for regulatory review. Methods Mol Biol 697:17–31CrossRefPubMed

21.

ADA (2013) Diagnosis and classification of diabetes mellitus. Diabetes Care 36(Suppl 1):S67–S74

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 185:2043–2051CrossRefPubMedPubMedCentral

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 176:3257–3265CrossRefPubMed

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 109:12668–12673CrossRefPubMedPubMedCentral

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 64:4198–4211CrossRefPubMed

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 34:854–862CrossRefPubMed

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 269:26–43CrossRefPubMedPubMedCentral

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 6:480CrossRefPubMedPubMedCentral

29.

Ravishankar B, McGaha TL (2013) O death where is thy sting? Immunologic tolerance to apoptotic self. Cell Mol Life Sci 70:3571–3589CrossRefPubMedPubMedCentral

30.

Yamashita U, Kuroda E (2002) Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit Rev Immunol 22:105–114CrossRefPubMed

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 69:2000–2009CrossRefPubMed

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 111:4215–4220CrossRefPubMedPubMedCentral

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 191:3049–3056CrossRefPubMed

34.

Scott CL, Aumeunier AM, Mowat AM (2011) Intestinal CD103⁺ dendritic cells: master regulators of tolerance? Trends Immunol 32:412–419CrossRefPubMed

35.

Belkaid Y, Oldenhove G (2008) Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity 29:362–371CrossRefPubMedPubMedCentral

36.

Getts DR, Shea LD, Miller SD, King NJ (2015) Harnessing nanoparticles for immune modulation. Trends Immunol 36:419–427CrossRefPubMedPubMedCentral

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 113:29–37CrossRefPubMed

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 100:8384–8388CrossRefPubMedPubMedCentral

39.

Irvine DJ, Swartz MA, Szeto GL (2013) Engineering synthetic vaccines using cues from natural immunity. Nat Mater 12:978–990CrossRefPubMedPubMedCentral

40.

Metcalfe SM, Fahmy TM (2012) Targeted nanotherapy for induction of therapeutic immune responses. Trends Mol Med 18:72–80CrossRefPubMed

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 117:5403–5412CrossRefPubMed

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 195:1289–1302CrossRefPubMedPubMedCentral

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 196:1091–1097CrossRefPubMedPubMedCentral

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 185:1595–1604CrossRefPubMedPubMedCentral

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 118:4853–4862CrossRefPubMed

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 109:3897–3902CrossRefPubMedPubMedCentral

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 27:3368–3382CrossRefPubMedPubMedCentral

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 60:2922–2927CrossRefPubMedPubMedCentral

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 116:3258–3265CrossRefPubMedPubMedCentral

Titel: Multipeptide-coupled nanoparticles induce tolerance in ‘humanised’ HLA-transgenic mice and inhibit diabetogenic CD8+ T cell responses in type 1 diabetes
verfasst von: Xinyu Xu
Lingling Bian
Min Shen
Xin Li
Jing Zhu
Shuang Chen
Lei Xiao
Qingqing Zhang
Heng Chen
Kuanfeng Xu
Tao Yang
Publikationsdatum: 08.09.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 12/2017
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-017-4419-8

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

25.04.2024 | Hypotonie | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

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

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Viel Bewegung in der Parkinsonforschung

Adjuvante Immuntherapie verlängert Leben bei RCC

Update Innere Medizin

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 12/2017

Assessment of glucose regulation in pregnancy after gastric bypass surgery

Improving the clinical value and utility of CGM systems: issues and recommendations

Spatial distribution of early red lesions is a risk factor for development of vision-threatening diabetic retinopathy

Gcg CreERT2 knockin mice as a tool for genetic manipulation in pancreatic alpha cells

South Asian men have lower expression of IFN signalling genes in white adipose tissue and skeletal muscle compared with white men

Erratum to: Understanding and preventing type 1 diabetes through the unique working model of TrialNet

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Viel Bewegung in der Parkinsonforschung

Adjuvante Immuntherapie verlängert Leben bei RCC

Update Innere Medizin