Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes

被引：151

作者：

Ali, Mohammad Alhadj ^{[1
]}

Liu, Yuk-Fun ^{[2
,3
]}

Arif, Sefina ^{[2
]}

Tatovic, Danijela ^{[1
]}

Shariff, Hina ^{[2
]}

Gibson, Vivienne B. ^{[2
]}

Yusuf, Norkhairin ^{[2
]}

Baptista, Roman ^{[2
,4
,5
]}

Eichmann, Martin ^{[2
]}

Petrov, Nedyalko ^{[4
,5
]}

Heck, Susanne ^{[4
,5
]}

Yang, Jennie H. M. ^{[2
]}

Tree, Timothy I. M. ^{[2
]}

Pujol-Autonell, Irma ^{[2
]}

Yeo, Lorraine ^{[2
]}

Baumard, Lucas R. ^{[2
]}

Stenson, Rachel ^{[1
]}

Howell, Alex ^{[1
]}

Clark, Alison ^{[1
]}

Boult, Zoe ^{[6
]}

Powrie, Jake ^{[3
]}

Adams, Laura ^{[3
]}

Wong, Florence S. ^{[1
]}

Luzio, Stephen ^{[7
]}

Dunseath, Gareth ^{[7
]}

Green, Kate ^{[8
]}

O'Keefe, Alison ^{[8
]}

Bayly, Graham ^{[8
]}

Thorogood, Natasha ^{[8
]}

Andrews, Robert ^{[8
]}

Leech, Nicola ^{[9
]}

Joseph, Frank ^{[10
]}

Nair, Sunil ^{[10
]}

Seal, Susan ^{[10
]}

Cheung, Hoyee ^{[10
]}

Beam, Craig ^{[11
]}

Hills, Robert ^{[12
]}

Peakman, Mark ^{[2
,4
,5
,13
]}

Dayan, Colin M.

机构：

[1] Cardiff Univ, Sch Med, Diabetes Res Grp, Cardiff CF14 4XN, S Glam, Wales

[2] Kings Coll London, Fac Life Sci & Med, Dept Immunobiol, London SE1 9RT, England

[3] Guys & St Thomas Hosp, Natl Hlth Serv NHS Fdn Trust, Dept Diabet & Endocrinol, London SE1 9RT, England

[4] Guys & St Thomas Hosp, Biomed Res Ctr, Natl Inst Hlth Res, London SE1 9RT, England

[5] Kings Coll London, London SE1 9RT, England

[6] Univ Hosp Wales, Clin Res Facil, Cardiff CF14 4XN, S Glam, Wales

[7] Swansea Univ, Diabetes Res Unit Cymru, Swansea SA2 8PP, W Glam, Wales

[8] Univ Hosp Bristol Fdn Trust, Joint Clin Res Unit, Bristol BS2 8HW, Avon, England

[9] Newcastle Upon Tyne Hosp NHS Fdn Trust, Diabetes & Endocrinol Dept, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[10] Countess Chester Hosp NHS Fdn Trust, Diabetes & Endocrinol Dept, Chester CH2 1UL, Cheshire, England

[11] Western Michigan Univ, Sch Med, Div Epidemiol & Biostat, Kalamazoo, MI 49008 USA

[12] Cardiff Univ, Sch Med, Haematol Clin Trials Unit, Cardiff CF14 4XN, S Glam, Wales

[13] Kings Hlth Partners Inst Diabet Endocrinol & Obes, London SE1 9RT, England

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2017年 / 9卷 / 402期

基金：

英国医学研究理事会;

关键词：

T-CELL RESPONSES; C-PEPTIDE; PRESERVATION; STIMULATION; ADOLESCENTS; SUPPRESSION; DEFINITION; PHENOTYPE; EPITOPES; CHILDREN;

D O I：

10.1126/scitranslmed.aaf7779

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigenDR4( DRB1* 0401)-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated b cell-specific CD8 T cells, and favorable b cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in b cell function, and is associated with antigen-specific and nonspecific immune modulation.

引用

页数：9

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